P Harm PK Archive

PharmPK
Archives
David Bourne, Ph.D.
PharmPK Archives
1995 - 96
These archives presents the discussions submitted to the

PharmPK ([email protected] http://www.pharmpk.com/) forum since November 1994.
The discussion submission have been only lightly moderated and have NOT been checked for accuracy. Some topics
are not complete, answers may be incomplete or even incorrect. Please dont base any clinical or medical decisions on
these discussion. Check citations and consult clinical and
medical references. Comments and corrections welcome,
David Bourne ([email protected])
2013 David W.A. Bourne, Ph.D.

i
1
1994
THE BEGINNING
Started in November 1994 after discussion at AAPS with

Brian Corrigan, a graduate student at the time. I had started a
website in February of that year and a listserv related to
pharmacokinetics seemed like a good idea.
OU Health Science had and has excellent internet connectivity
and I had software that ran easily on my little Macintosh.
Apache webserver, macjordomo listserv software and a home
grown Fortran program to create the archive pages.
AAPS, PPDM Section Service Award 2006
Now (Jan 2013) over 3,750 (email addresses) members
Plain text messages to [email protected] are lightly
moderated
The archives are a collection of these messages with time
sensitive (job advertisement/conference notes) removed. They are
available online at http://www.pharmpk.com/
S EC T I O N 1
Lag in Urine Clearance - Urine/Plasma

Correlation
On 27 Dec 94
I have a problem that is just the sort of thing that should be bounced o of a hundred plus
pharmacokineticists. I am conducting a study on renal clearance of a drug. Analysis is
done on the timed urinary output of the subjects over a 48 hour period. In virtually every
subject, the first peak is detected 5 hours post-administration. A second peak, 80-120% of
the first peak, is detected at 10 hours post-administration. The drug is excreted 97% in
urine and my analysis procedure converts all conjugates into free drug. The time lag between the two peaks is too long for enterohepatic recycling and too high for CSF dumping. For most of the subjects, the timing of the peaks correspond to 1:00 and 6:00 pm,
but the same relative timing post-dose is observed in subjects taking their dose at 4:00 am
and at noon.
Has anyone else observed a 5 hour lag between peaks in urine or serum analysis? If so,
were you ever able to explain its origin? I will entertain any and all explanations barring
alien interaction and sunspots.
Kris Holt
On 27 Dec 94
I assume you are measuring steadily decreasing amounts of drug excreted into urine from
the start but are seeing abnormal increases ('peaks') at 1 and 6 pm (in most of the subjects).
If a meal is given at say 12 noon - 2 pm and 5 - 7 pm recycling may explain your results. Bile
dumping could result from a meal or anticipation of a meal. My guess - anyone else?
What sort of assay are you using?
On 27 Dec 1994
There is a possibility that a window of absorption exist for this drug in the more distal and
perhaps in the large intestine?
Majid Vakily
On 27 Dec 1994
First and foremost you seem to think that the second peak in urine output of the drug is
due to the bodies handling of the compound and is unrelated to the formulation of the
drug (enterohepatic cycling), if this were the case then you should see a double peak with
dose of oral solution or an immediate release prep. Do you see a double peak in this case?
Are double peaks reported for IV bolus? I know that this sounds really stupid, but have
you checked to make sure that you are doing your calculations correctly and are not somehow making a erroneous calculation that leads to a higher than expected calculation in
rates of urine excretion? Had to ask that one since it would be such an easy explanation.
Until you dose some people with a oral solution or IV bolus I don't think you will be able
to say much of anything about what is going on. Next question is did you see double
peaks in every bodies profile? How many people were dosed? Was everyone fasted or did
people have food also? How was the drug dosed, with water? Of course cimetidine is the
great example of a double peak. In the case of cimetidine the magnitude or presence of
the double peak is variable. I think that it would be surprising if you saw TOO much consistency in your data. Finally more stupid questions, are you sure that some of what your
seeing could be due to urine collection and or handling methods? Were the same type of
containers used through the entire period? Assay methods validated with these containers? I am thinking that you may want to think about surface-binding with containers, etc.
(Pretty far-fetched, right?). Finally on the handling trail, what about the hydration of people in the study? Were study subjects allowed water? Is the drug reabsorbed in the kidney?
I think that you need to do the oral solution thing before you do anything else. More than
likely what you are seeing in phenomenon that is due to the absorption of drug from the
dosage form. Have you tried a similar drug in the same formulation?
On 3 Feb 1995
Can anyone suggest a few good papers on the correlation of plasma concentration/time
data to urinary excretion? I'm interested in data for drugs in which nearly all excretion
(i.e. 95-100%) is through the kidneys, either as parent compound or as a simple metabolite such as a glucuronide. Urinary excretion could be represented by dU/dt, cumulative
recovery, or percent left to be excreted. Any help on this subject would be greatly appreciated.
Kris Holt
On 3 Feb 1995
You may want to look at some recent papers dealing with the pharmacokinetics of sotalol.
Rob Carr, a fellow graduate student working with me in Dr R.T. Fosters lab, has done extensive research into the pharmacokinetics of this compound which is eliminated almost
exclusively by the kidneys.
John Grundy
On 6 Feb 1995
There is an excellent textbook by Evans, Schentag & Jusco: Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring, Applied Therapeutics Inc., Vancouver, WA,
3rd Ed., 1992 that contains lots of information about renal function and drug clearance.
You may find it useful.
A not so recent paper - that I co-authored - is: J.Wol, D.Bigler, C.B.Christensen,
S.N.Rasmussen, H.B.Andersen & K.H.Tnnesen 1988 Influence of renal function on the
elimination of morphine and morphine glucuronides, Eur. J. Clin. Pharmacol., 34, 353-357.
Soren Norgaard Rasmussen
S EC T I O N 2
Pharmacodynamic/Pharmacokinetic Software
On 30 Nov 94
In an attempt to get some sort of dialogue going I'm going to ask about PK/PD computer
packages that you all use.
What, if any, software do you use? What doesn't it do that you would like it to? What platform does it run on? What platform would you like it to run on?
I don't want this to turn into a MyFit is better than YourFit argument but I'm sure many
of us would be interested to hear YOUR views.
Frank J Hollis
On 30 Nov 1994
Its nice that somebody finally break the ice. The programs we normally use are PCNONLIN and Lagran. A combination of the two are usually enough to take care of our conventional data analysis. With PCNONLIN, we often find that sti data are not well fit.
With LAGRAN, there is a problem of handling a huge data set. We are also experimenting with MATLAB, a program frequently used by chemical engineers. Initial experience
tells us that this program can be used to handle complicated models.
This is a start, I hope we can hear more from the other people.
Yun Tam
On 30 Nov 1994
In addition to using PCNONlIN and Lagran we have used MKMODEL and JANA in
our laboratory to model data. Does anyone else have experience with using other
modeling programs that are user friendly and ecient? In addition, members of our laboratory have been using neural network programs to predict drug concentrations does any6
one have any experience with these programs? Brainmaker seems to be a good neural net
program that is relatively easy to run what other programs are commercially available?
Neal Davies
On 1 Dec 1994
I use MKMODEL to explore complex models and for quick turn around on simple problems.
I use NONMEM for all population analyses. For me there are no other choices :-)
Nick Holford
On 30 Nov 1994
In our lab. we routinely use pcnonlin for data fitting and analyzing our data. Lagran is another software that we use occasionally. Pcnonlin, however, is the main software. we have
done some linked PK/PD modeling using this software. As Dr.Tam mentioned sometimes
is really is time consuming to work we this software. recently we are trying to start learning nonmem. Furthermore, NN seems a good package. I personally would like to learn
about matlab more. This package seems is good for handling complicated modeling. I
would appreciate if somebody sends me some information about this software (supplier,advantages,disadvantages.)
Majid Vakilynejad
On 1 Dec 1994
We use the same program for both pharmacokinetic/pharmacodynamic analysis and neural
network predictions, FUNFIT. Unfortunately, it is not commercially available and is not
user friendly, but it is powerful enough to meet our needs at the University of Iowa.
Ron Herman
On 2 Dec 1994
I just ran into a commercial package entitled "Scientist" from Micromath. The package is
billed as an "...integrated software for experimental data fitting" (runs under Windows).
The examples look at PK problems, model dependent and model independent examples
are included.
I have just purchased the product. After "playing" with it for several weeks I will report
back on its usefulness
On 2 Dec 1994
With regard the survey of pkin software I would like to tell you that I am trying to maintain a WWW page listing many such software programs. If you would like to send me (at
[email protected]) more information on any such pk/pd software package I'd be happy to
add it to the WWW page(s). Try: http://www.pharmpk.com/soft.html
David Bourne
On 2 Dec 1994
We have tried to stay current with the advances of the pkin software, but have not yet
had any experience with neural networks. I would be interested in either a public or private discussion of the use/necessity of this system.
I do my initial data entry and manipulation with PSI-Plot from Poly Software International (Utah, ver. 3.0). Others in the department use Excel. Most of us use RSTRIP for
fitting. I am also using Gillespie's PCDCON for deconvolution of urinary excretion data.
Kris Holt
On 2 Dec 1994
In our lab we have been using the programs BOOMER/MULTIFORTE for modeling PK/
PD data. They are user friendly and can be used for simple models to complex models.
They can be used for physiological modeling too. The programs perform simulation and
fitting and includes Bayesian optimization. Models and integrated or dierential equations can be expressed as a sequence of parameters in BOOMER or using Fortran state8
ments in MULTIFORTE. Supplied as compiled programs for Macintosh, MSDOS and

VAXVMS systems. Would like to know if any of you have used these programs and your
experiences with them.
Brinda Koneru
On 3 Dec 1994
You have mentioned about a software called funfit. Is it possible that you kindly provide
me with more information about this program?
Majid Vakilynejad
On 4 Dec 1994
Since we are on the topic of pk/pd software I would like to know what type of software
people are using for chromatographic analysis with their HPLC's. We are using E-ZChrom which has not proven to be user friendly at all. Other labs in our Faculty have
been using Milenium. What other software is commercially available and is being used
out there?
Neal Davies
On 6 Dec 1994
Re the recent posting about software for HPLC, I thought I might inform you that the
Hungarian company CompuDrug Chemistry, Ltd. produces a programme called EluEx, designed to assist in HPLC method development for C-18 RP-HPLC. EluEx suggests the optimal mobile phase composition for separation, and includes a pKa calculating module as
well as graphical simulation of the chromatogramme.
For details, contact Dr. Zoltan Bencz at
CompuDrug Chemistry, Ltd., Furst Sandor utca 5, H-1136 Budapest, Hungary
Internet: [email protected]
Dr. S. Shapiro
9
On 9 Dec 1994
Where can I find information on clinical pharmacokinetic softwares or programs for use
in clinical settings?
Pierre-Paul Leblanc
On 27 Dec 1994
What simulation software/languages are being used out there? Has anyone heard of a language specifically for simulation called SIAM or SLAM? I've also heard that there is an
internet users group for simulation similar to this for PK Any ideas about this? How
about vendors for simulation software?
Mark Sale
On 3 Jan 1995
We are using:
1.
Simusolv, a superset of ACSL which also does fitting, excellent but very expensive (running on SPARCstation).
2. Stella II on pc or Mac (has interesting features but limited by the numerical algorithms it uses, verify your results with another package if possible).
3.
NONMEM (for population simulations).
4. ADAPT II
William Bachman
On 10 Jan 1995
There is a specific simulation program called SAAM which originated from the NIH and
was available in the 70s on mainframe. I understand it is now available for the pc but I do
not know the source of it. Maybe NIH would know. To my knowledge this program was
custom designed for simulations same as NONLIN is custum designed for data fitting.
Iqbal Ramzan
10
On 10 Jan 1995
If you have an interest in SAAM, you should contact Loren A. Zech at the NIH. He has
been largely responsible for the continued development and distribution of this software.
The latest version I know of is SAAM31.
His address is: Loren A. Zech. Lab of Mathematical Biology, NCI, NIH, Bethesda, MD
20892
Ron Sawchuk
On 10 Jan 1995
I have used STELLA quite a bit for simulation of pharmacokinetic systems for teaching
and research. I have taught an elective course in pharmacokinetic simulation to pharmacy
students for 4 years at the University of Minnesota , and find that the animation component makes it a great instructional tool. It allows for sensitivity analysis, as well.
STELLA was developed for the Mac, but is now available for the Windows environment.
STELLA II vers 3.0.5 is marketed by High Performance Systems, Hanover NH.
Ron Sawchuk
On 10 Jan 1995
In reply to Iqbal Ramzan's and Ronald Sawchuk's responses to Mark Sale's query regarding
simulation software:
SAAM/CONSAM is available for the PC from either Loren Zech at NIH (or David Foster at the University of Washington). More information about the NIH program (and the
program itself) may be obtained at http://www.ncifcrf.gov:2001/~grief/info.html
If this doesn't work, try http://www-lmmb.ncifcrf.gov/~grief/info.html
[NOTE: At 14 Apr 95 the URL http://www-saam.nci.nih.gov/ seems like a good
starting point. db]
The NIH and washington versions of CONSAM are NOT THE SAME. Primarily, they
dier in the way they do screen graphics. Both use the original SAAM numerical algo11
rithms (circa 1960's). Foster's group has just released SAAM II for Sun workstations with
PC and Mac versions to follow. For information, I'd suggest contacting Dr Foster at the
above address.
William F. Beltz, Ph.D.
On 20 Jan 1995
I'm Director of Pharmacy at Brookside Hospital in San Pablo (Bay Area). Several years ago
I wrote a basic program to help dose patients on aminoglycosides. I have recently made it
available as Freeware on the Net. Also included is Gentex.Doc, the documentation.
I don't know how useful this will be to the members of this list as it seems that most of
you are Unix based researchers, but it's there if you want it.
Neil Sandow, Pharm.D.
12
S EC T I O N 3
Neural Net Software

On 1 Dec 1994
I would love to get some information about the Brainmaker. Do you have any references
that you might be able to quote?
Chetan D. Lathia
On 1 Dec 1994
We use the same program for both pharmacokinetic/pharmacodynamic analysis and neural
network predictions, FUNFIT. Unfortunately, it is not commercially available and is not
user friendly, but it is powerful enough to meet our needs at the University of Iowa.
Ron Herman
On 2 Dec 1994
Frank Hoke (Glaxo Research Institute: 919-990-5157) will be hosting a seminar at next
years AAPS meetings on neural nets. Ward Systems Group has some software for PK/PD
that you may be interested in looking at.
On 2 Dec 1994
Could somebody thro' some light on the 'Application of Neural Nets in PK/PD' ..any relevant papers/publications/programs...
Jagadeesh Aluri
13
On 2 Dec 1994
This is by no means complete, but it is a place to start:

1.
Erb RJ 1993 Introduction to backpropagation neural network computation. Pharm Res

10, 165-170
2. Hussain AS, Johnson RD, Vachharajani NN and Ritschel WA 1993 Feasibility of developing a neural network for prediction of human pharmacokinetic parameters from animal data. Pharm Res, 10, 466-469
3.
Veng-Pedersen P and Modi NB 1993 Application of neural networks to pharmacodynamics. J Pharm Sci, 82, 918-926
4. Veng-Pedersen P and Modi NB 1992 Neural networks in pharmacodynamic modeling.

Is current modeling practice of complex kinetic systems at a dead end? J Pharmacokin
Biopharm, 20, 397-412.
Ron Herman
On 2 Dec 1994
A few comments regarding neural networks for PK/PD applications:

1.
The delta-backpropagation network should be considered to be a "multiple nonlinear

regression analysis" tool which does not require a user to define the function.
2. Suciently large data base is generally needed for network training and validation.
3.
The trained network should be used as a simulation tool to identify relationships between input and output variables. These relationships can be used for more "formal"
model building or hypothesis testing.
4. Research is needed for developing indicators or metrics for network performance.

Without these use of neural networks will be limited to "informal" data analysis.
Ajaz Hussain
14
On 2 Dec 1994
Our lab has had some success using a neural network package from California Scientific
(Palo Alto, California). Someone previously mentioned that Ward Systems has Specific
softwre for Pk/Pd analysis. Could anyone elaborate on this further?
Brian Corrigan
15
2
1995
16
S EC T I O N 1
Alcohol pks
On 18 Oct 1995 at 22:27:51
Peter,
I would appreciate receiving any available information (especially references) concerning the absorption of alcohol (ethanol) in humans. What is an accepted Ka value for
alcohol? Most papers in the forensic literature focus on the time of the peak BAC and
then, in effect, treat alcohol absorption as a zero-order process (with parameters dependent upon the type of alcoholic beverage consumed).
You might take a look at a review on ethanol PK in Clinical Pharmacokinetics 1987;

13:273-292 for an overview of absorption models. A simple first-order absorption model (as
implied by your request for an 'accepted ka') is probably as inappropriate as asking for an 'accepted half-life' for ethanol i.e. models which describe ethanol input and elimination usually
need to be more sophisticated than the elementary first-order one compartment stuff. But it
depends on your application of the model how fancy you need to be. Ethanol has rate dependent extraction when taken orally (probably in the liver - I don't accept the gastric ADH
hypothesis). So if you really want to model oral absorption you cant assume the extent of absorption will be independent of absorption rate.
-Nick Holford
Dept Pharmacology & Clinical Pharmacology University of Auckland, Private Bag 92019,
Auckland, New Zealand http://www.phm.auckland.ac.nz
On 22 Oct 1995 at 11:21:47
Maybe I'm all wet, but if you're looking for a Ka for EtOH, it would seem that you would
have to separate the absorption component from the elimination portion. Saturation of the
elimination mechanism would be needed. At that point, you could do a comparison between
oral absorption and IV infusion. (as long as you had a big enough sample population)
Bob Brennan
17
On 28 Oct 1995 at 21:21:43
Take for example, treatment of a methanol overdose. Ethanol treatment can be very close
to the enzyme saturation point. If at that point, you converted from IV EtOH to PO EtOH,
wouldn't that give you some decent ka info?
Bob Brennan
18
S EC T I O N 2
Aminoglycoside stability
On 18 Dec 1995 at 09:44:42
Does anyone have any information on the stability of aminoglycoside solutions stored at
-20C
The UK NEQAS for Antibiotic Assays is provided by:
Department of Microbiology, Southmead Health Services NHS Trust, Bristol BS10 5NB,
UK.
http://www.ibmpcug.co.uk/~lwhite/index.html
Dr Les White
On 19 Dec 1995 at 13:34:41
Check the reference of Brown et al. 1991 on gentamicin in J Assoc Off Anal Chem. It provides stability of gent at various temperatures and pHs.
Rob Hunter
19
S EC T I O N 3
Analytical Methods for Moisture

On 25 Oct 1995 at 10:34:39
Anyone familiar with Karl Fischer method for determining moisture content.
Where can I become familiar with his studies?
On 26 Oct 1995 at 19:05:13
There is a full description in the section of 'Water

determination' of USP 23, p.1840 (mine is Asian edition), 1995.
YJ Lee
On 26 Oct 1995 at 19:05:17
The following book has a very good summary on KF method:

Douglas A. Skoog, Donald M. West: Fundamentals of Analytical Chemistry,3rd
Ed.,Holt, Rinehart and Winston, 1976, p. 607-610
For review on the subject of KF reagent also see J. Mitchell, Anal.Chem.,23, 1069 (1951) and
J. Mitchell and D.M. Smith, Aquametry. New York; Interscience Publishers, Inc., 1948
Also, I'd suggest you to examine the United States and British Pharmacopaeias.
Good luck,
Andrej Skerjanec
HPB, Ottawa
20
S EC T I O N 4
Blinding Clinical Studies

On 21 Nov 1995 at 16:07:00
We are conducting a clinical study using a combination of drug A and drug B or placebo in
tablet formulations. We wish to blind this study by placing these tablets in a container for
oral administration.
The historical device 'cachet' has been suggested. A cachet ranges in size from 3/4 to 1/8
inch in diameter and consists of two concave pieces of wafer made of flour and water. They
are sealed by moistening the margins and pressing pressing firmly together. Are these available? We need approximately 11,000 of them.
Please share any experience regarding blinding techniques.
Thank-you for your assistance.
Derek A. Ganes, Ph.D.
Director, Biopharmaceutics, Biovail Corporation International, Contract Research Division,
460 Comstock Road, Toronto, Ontario, Canada M1L 4S4
On 22 Nov 1995 at 10:48:14
Tablets in a capsule are the normal blinded supplies for this kind of study.
M Chasin
On 27 Nov 1995 at 10:49:48
Thank-you for your comments regarding the use of tablets in capsules for the blinding of
clinical supplies.
Unfortunately, the tablets can not be put in a reasonably sized capsule because of the large
diameter of one of the tablets. This is why the 'cachet' was suggested.
Biovail Corporation International
21
On 28 Nov 1995 at 14:04:15
In France, 'cachet' is still available. I know a company which can provide you what you want :
Jacques Trevidic
Cooperative Pharmaceutique Francaise, 32 Bd Victor Hugo, BP 294, 44010 NANTES,
FRANCE
On 29 Jan 1996 at 13:37:37
I meant to tell you that Capsugel have a range of shells suitable for your need.
Izzy Kanfer
22
S EC T I O N 5
Convolution and Deconvolution techniques to

assess Bioavailability
On 18 Dec 1995 at 09:44:40
Can someone explain what these techniques are? Where these should be used and what are
the advantages/disadvantages of using these techniques.
Please also post any references and/or books about these techniques.
Thanks
Masood Bhatti
Faculty of Pharmacy, University of Alberta, Edmonton, Alberta, Canada
On 18 Dec 1995 at 14:23:44
Convolution and deconvolution techniques are not necessarily used to answer the question of
bioavailability. The Wagner Nelson method and Loo-Reigelman methods are forms of deconvolution. Deconvolution techniques are used to assess rates of absorption and require
I.V. data. Some names to get you started are W. J. Jusko and P. V. Peterson.
However, this is a fairly complicated subject.
Steve Bramer
On 19 Dec 1995 at 13:34:42
Convolution and deconvolution techniques are not necessarily used to answer the question of bioavailability. The Wagner Nelson method and Loo-Reigelman methods are forms
of deconvolution. Deconvolution
Same area but slightly different direction. I had thought of WN and LR as specialized examples of deconvolution and had included them as such under Deconvolution in my book
which was published earlier this year. One reviewer expressed the opinion that this was incorrect. Do any others on the PharmPK list have an opinion about this? Thanks.
David Bourne
23
On 19 Dec 1995 at 13:34:44
Dear colleague,
All arguments presented below are based on the assumption that the disposition kinetics of
the drug is linear.
The drug bioavailability in the circulatory system after extravascular administration is defined in two ways, i.e. as the extent of bioavailability and the rate of bioavailability (1).
The system describing the drug input into the circulatory system after extravascular administration can be defined in the Laplace s-domain by Eq.1
H_{c}(s) = X_{c}(s)/Y_{ex}(s)!
(1)
where H_{c}(s), X_{c}(s) and Y_{ex}(s) are the system transfer function, output and input, respectively (2). X_{c}(s) represents the drug input into the circulatory system. Since
this input is not available for measurement, to estimate the system transfer function the following systems can be used:
The system describing the drug input into the circulatory system after intravascular administration can be defined in the Laplace s-domain by Eq.2
H_{iv}(s) = X_{p,iv}(s)/Y_{iv}(s)!
(2)
where H_{iv}(s), X_{p,iv}(s) and Y_{iv}(s) are the system transfer function, output and
input, respectively. X_{p,iv}(s) represents the peripheral system output. The system describing the drug input into the circulatory system after extravascular administration can be defined in the Laplace s-domain by
Eq.3
H_{ex}(s) = X_{p,ex}(s)/Y_{ex}(s)!
(3)
where H_{ex}(s), X_{p,ex}(s) and Y_{ex}(s) are the system transfer function, output and
input, respectively. X_{p,ex}(s) represents the peripheral system output.
Since
H_{ex}(s) = H_{iv}(s).H_{c}(s)!
(4)
the transfer function H_{c}(s) can be expressed in the form of Eq.5, using the definitions
given by Eqs.2 and 3
H_{c}(s) = (X_{p,ex}(s).Y_{iv}(s))/ (X_{p,iv}(s).Y_{ex}(s))! (5)
For the equal inputs,

Y_{iv}(s)=Y_{ex}(s)
(6)
Eq.5 can be rewritten in the simple form of Eq.7

H_{c}(s) = (X_{p,ex}(s))/(X_{p,iv}(s))!
(7)
Eqs.5 and 6 enable to estimate the drug bioavailability on the basis of the measured functions X_{p,ex}, Y_{iv}, X_{p,iv} and Y_{ex}. The gain parameter (2) of the model of
the transfer function H_{c} approaches the extent of the drug bioavailability. The model
24
of the weighting function, corresponding to the model of this transfer function approaches the rate of the drug availability after extravascular administration.
In the specific case of equal intravascular and extravascular inputs (Eq.6), the weighting
function can be estimated using deconvolution methods in the time domain. The literature
on numerical and analytical deconvolution methods is extensive. Analytical deconvolution
methods are mostly devoted to relatively simple models (3) which do not contain shunt
and time delays and which models of transfer functions do not contain complex poles (2,4).
The CXT program, described in our study (5) and available at
http://www.pharmpk.com/soft.html
option: software,
enables to estimate the system weighting function for equal and/or non equal intravascular
and extravascular inputs.
Sincerely,
Dedik, Ladislav
Durisova, Maria
REFERENCES
1. Wagner, J.: Fundamentals of Clinical Pharmacokinetics, The Hamilton Press, Inc.
Hamilton, Illinois, 1975.
2. Dedik, L., and Durisova, M.: Frequency response method in pharmacokinetics. J.
Pharmacokin. Biopharm., 22, 1994, 293-307.
3. Gillespie, W.R., and Veng-Pedersen, P: A polyexponential deconvolution
method. Evaluation of the "gastrointestinal bioavailability" and mean in vivo dissolution time of some ibuprofen dosage forms on appropriate constraints on the initial input response when applying deconvolution. J. Pharmacokin. Biopharm., 13, 1985,
289-307.
4. Dedik, L., Durisova, M., and Balan, M.: Building a structured model of a complex
pharmacokinetic system with time delay. Bull. Math. Biol., 57, 1995, 787-808.
5. Dedik, L., Durisova, M.: CXT - a programme for analysis of linear dynamic systems in
the frequency domain. Int. J. Bio-Med. Comput., 39, 1995, 231-241.
25
On 20 Dec 1995 at 13:52:51
Wagner-Nelson is considered a specialized (read limited ?) form of deconvolution. Limited

to a single compartment analysis with first order absorption. Application of convolution
of deconvolution does not require a compartmental assumption. Other assumptions do
apply.
Deconvolution can be used to characterize the absorption profile (and hence assess bioavailability) among other things. And deconvolution does not require that an intravenous
administration to be applied. It depends on the question!
Nishit Modi.
On 10 Jan 1996 at 13:09:08
I consider LR and WN as parametric forms of deconvolution. However, I also consider

conventional nonlinear regression to be a method of parametric deconvolution when it is
used to identify a disposition function.
Steve Shafer
On 19 Jan 1996 at 11:14:32
For the linear dynamic system defined by the weighting function WF(t), input function I(t) and output function O(t), the system output can be expressed by Eq.1
O(t)=f1(I(t), WF(t))!
(1)
where t represents time.

The function f1 is the convolutory integral. The system weighting function and the system input can be expressed in the form of Eq.2 and Eq.3, respectively
WF(t)=f2(I(t), O(t))!
(2)
I(t)=f3(WF(t), O(t))!
(3)
The methods for determination of the system weighting function and the system input on the basis of Eq.2 and Eq.3, respectively, are called deconvolution methods.
The Wagner-Nelson method enables to determine the system input I(t) if the mathematical model of drug elimination is known and if the system output O(t) can be measured after extravascular administration. This method enables to reach the same result as
26
does Eq.3 but it does not employ the properties of the convolutory integral. It follows
then that, in principle, the Wagner-Nelson method is not a deconvolution method.
However, it is obvious that if the known mathematical model of the drug elimination
has the weighting function WF(t), then the same result is obtained whether the deconvolution method based on Eq.3 or the Wagner-Nelson method is used.
Dedik Ladislav, Durisova Maria
27
S EC T I O N 6
Double Sites Kinetic - Software

On 21 Feb 1995
Hello to the recipients of the pharmacokinetic List,

For my data, I'm looking for software (Mac is preferred) which could fit them according a
double sites (with no cooperatively) Kinetic. Do somebody have informations where I
could find it on the net (ftp site ?)
Hugues Abriel
On 2 Mar 95
I have some software, Boomer, which runs on the Mac and does PK analyses. What sort
of equations do you mean by 'double sites'. Two enzyme sites? I have the manual on my
WWW server:
http://www.boomer.org/
I have free versions available for download. If you don't see you model in the descriptions
let me know what your equation look like.
David Bourne
On 2 Mar 95
For nonlinear least-squares curve-fitting (of any (!!!) model, 1- and 2-sites, pharmacokinetics, pharmacodynamics) I am perfectly happy with Systat 5.03, in particular the Simplex
optimization. Systat is one of the big commercially available packages (SPSS is the other)
and is also available in a Mac-version. Systat is produced and sold by Systat Inc., 1800
Sherman Avn., Evanston, IL 60201-3793, USA, tel. +1 (708) 864 5670, fax. +1 (708) 492 3567.
There will probably be a representative in CH.
Andries Koster
28
S EC T I O N 7
Frequency response method

On 17 Mar 95
I would like to invite your attention to applications of the frequency response method to
pharmacokinetics (1-4). The frequency response method, common in system engineering,
is based on an approximation of the frequency response of a linear dynamic system,
calculated from input-output measurements, by a frequency model of the system transfer function in the frequency domain. In general, the influence of the system structure on
the form of the system frequency response is much more distinct than on the form of
the system output. This is of great advantage in modeling the system frequency response instead of the system output, commonly used in pharmacokinetics.
1.
Dedik, L. and M. Durisova 1994 Frequency Response Method in Pharmacokinetics. J.

Pharmacokin. Biopharm. 22, 293-307.
2. Durisova, M. and L. Dedik 1994 Comparative Study of Human Pentacaine Pharmacokinetics in Time and Frequency Domain. Meth. Find. Exp. Clin. Pharmacol. 16, 219-232.
3.
Durisova, M, Dedik, L, and Balan, M. 1995 Building a structured model of a complex

pharmacokinetic system with time delays. Bu!.Math.Biol., accepted, in press.
4. Dedik,L. and M.Durisova 1995 CXT-A Programme for Analysis of Linear Dynamic
Systems in the Frequency Domain. Int. J. Bio-Med. Comput., accepted, in press.
Maria Durisova
29
S EC T I O N 8
HPLC Standard Curve

On 6 Dec 1995 at 14:12:38
Dear Pharmacokineticists,
I am a Masters by Research student who is studying pharmacokinetic data of cancer
drugs in humans. My background is Statistics, and some of the things you may take for
granted, we don't. I have a question:
I would like to know whether, in general, an intercept is fitted to a HPLC standard
'curve'. I see that sometimes it is forced through the origin and then sometimes it is not. It appears that the intercept is also often not significant in the regression, however this is usually
insufficient grounds for removing it. It's better to have a physical reasoning. As far as I've
been told, no-one knows what happens between the lowest measurable concentration and
zero. It's definitely not a straight line. But at zero concentration, the peak should be zero (obviously), however that again is insufficient grounds for removing the intercept. It also appears
that fitting an intercept allows a better fit to the three or four values that make up a 'standard'.
Lukas Zdanius
On 8 Dec 1995 at 10:39:05
In our company, there are strict guidelines about not forcing the intercept through zero. The
range of quantification is bounded by nonzero calibration standards. Weighted linear regression is used to fit the range if an unweighted fit is unsatisfactory. The limit of quantification
is the lowest calibration standard that, upon back-calculation, gives satisfactory precision and
accuracy results.
A useful general guide may be found in J. Pharm. Sci., 81(3):309-312, 1992, or J. AOAC Int.
75(1):19A-26A, 1992.
Varun Garg
30
On 11 Dec 1995 at 10:46:11

I would like to know whether, in general, an intercept is fitted to a HPLC standard
'curve'.
Dear Luke,
A standard curve is valid only between the lowest and highest concentrations. The regression
should not be forced through the origin (how do you know the curve is linear below the lowest standard concentration) nor should the standard curve be extrapolated below the lowest
concentration - or above the highest. Thus, the intercept of a standard curve is unimportant.
To estimate concentrations lower than your lowest standard, you must choose a new lower
standard concentration and include it in your standard curve.
Jo Cato
On 11 Dec 1995 at 12:24:44
Hi Dear Luke,
With regard to including or excluding the intercept from the Std. curve, you should consider
the magnitude of the intercept compared to the ratio of drug/IS for the lowest
concentration that you have in your std. calib. curve. In general, if the intercept is 10 times
smaller than the mentioned ratio, one can simply omit that from the estimation of
concentration of the unknown samples. However, if the intercept is relatively high and/or inclusion of intercept decreases the error of estimation of unknown samples within a run, one
should consider the intercept.
M.Vakily
Faculty of Pharmacy and Pharmaceutical Sc., University of Alberta, Edmonton, Alberta,
Canada
On 11 Dec 1995 at 12:24:45
I'm not certain if this is helpful or not. I am currently in a pharmacometrics fellowship and
still learning, but here goes..
I have had the pleasure of attending Dr. Roger Jelliffe's Population PK/PD course. One of
the books he gives out is about characterizing the error patterns of assays. It's whole title is
'Pharmacoinformatics: Equations for Serum Drug Assay Error Patterns; Implications for
Therapeutic Drug Monitoring and Dosage.' It talks about polynomial descriptions of assay
error.
Robert M Shore
31
On 13 Dec 1995 at 14:09:28
There are 'right answers' here but probably the most important thing to do is what has already been done here i.e. to think about your particular problem and ask if an intercept is
reasonable. I agree that the theoretical predication is that the peak should be zero when conc
is zero but it is possible to have a systematic error at zero e.g. by not calibrating the machine
properly. But I think the main issue here is the nature of the error model not the structural
model. An error model that predicts the variance of the peak at each conc can be constructed that say makes the variance proportional to the predicted peak squared plus an additive component which allows for the error (mean zero) at a conc of zero. Software that allows
this and other more flexible variants of this error model has been around for a while but I
dont know if many conc analysts (as opposed to data analysts) are aware of that.
-Nick Holford, Dept Pharmacology & Clinical Pharmacology, University of Auckland, Private Bag 92019, Auckland, New Zealand, http://www.phm.auckland.ac.nz
On 13 Dec 1995 at 14:09:31
Thanks for all the responses regarding whether an intercept should be fitted to a HPLC
curve. I received about 14, and will reply to each one in time. It appears that there is stronger
grounds for keeping the intercept.
Lukas Zdanius
School of Statistics
32
S EC T I O N 9
Nicotine Patch and Cotinine Measurements

On 24 Aug 1995 14:49:50
We use urinary and salivary cotinine levels to assess the degree of study subjects' compliance with smoking cessation protocols. A new protocol may involve use of nicotine
patches. I presume this would invalidate the use of cotinine monitoring to assess compliance, but are there data already about the relationships of cotinine levels to transdermal
nicotine? Does anyone have experience with other techniques to determine how much a
subject is / is not smoking?
Marcel J. Casavant, MD
Children's Hospital, Columbus OH
On 24 Aug 1995 17:23:17
We used CO analyzers for our nicotine patch/I.V. studies here at Maine

Jim Cotter
Clinical Research Mgmt., Medical Center Research Institute.
On 29 Aug 1995 22:41:35
We have used cotinine levels in our clinical pharmacology studies to determine if a subject
smokes, or has been exposed to smoke. It turns out that although our lab reference range
lists >50 ng/ml to be upper limit of normal, many of our subjects have levels of 100-200
ng/mL. Although the subjects deny smoking, passive exposure to smoke is something you
will have to deal with. You should ask yourself if it is compliance that you want to document or the actual quantitation of nicotine systemic exposure.
J Paul
33
S EC T I O N 10
Pharmacokinetics of Lamotrigin
On 3 Feb 1995
Hello All.
I would like to know if somebody has information on population pharmacokinetic data
on a new anti-epileptic drug: LAMOTRIGIN?
Soren N. Rasmussen
On 3 Feb 1995
1. M.K.Yau, T.H.Grasela, J.B.Fiedler-Kelly, E.Cox, A.A.Lai, G.P.Womble, J.P.Hubbell. Population Pharmacokinetics of Lamotrigine from Three Add-on Controlled Clinical Trials in
Adult Patients with Epilepsy. Abstrast presented at American Epilepsy Society Annual
Meeting, Sheraton Bal Harbour Hotel, Miami, Florida, December 3-9, 1993.
2. J.B.Fiedler-Kelly, T.H.Grasela, M.K.Yau, L.Philips, S.Spencer, D.A.Smith, A.A.Lai. Lamotrigine Population Pharmacokinetics from Three Add-on Open Clinical Trials in Pediatric Patients with Epilepsy. Abstrast presented at American Epilepsy Society Annual Meeting, Sheraton Bal Harbour Hotel, Miami, Florida, December 3-9, 1993.
3. M.K.Yau,A.A.Lai, G.P.Womble, W.A.Wargin, T.H.Grasela, J.B.Fiedler-Kelly Lamotrigine Pharmacodynamics in Adult Patients - Safety and Ecacy. Abstrast presented at
American Society for Clinical Pharmacology and Therapeutics Annual Meeting, New Orleans Marriott, New Orleans Louisiana, March 30-April 1,1994.
4. M.K.Yau, A.A.Lai, J.B.Fiedler-Kelly, T.H.Grasela. Logistic Regression Analyses of Lamotrigne Pharmacodynamics in Adult Patients with Epilepy Enrolled in Three WellControlled Add-on Clinical Trials. Abstrast presented at American Epilepsy Society Annual Meeting, Sheraton New Orleans Hotel, New Orleans, Louisiana, December 2-8, 1994.
Brian Sadler
34
S EC T I O N 11
Pharmacokinetics and MathCad

On 1 Dec 1995 at 11:49:47
Does anyone have a library of pharmacokinetic functions for MathCad they would be willing to share?
Thanks
Merlin V. Nelson
On 4 Dec 1995 at 17:21:37
Hi Merlin,
I have MathCad programs for simulating two simple models: multiple-dose, 2compartment model, first-order absorption with a lag-time; multiple-dose, 2-compartment
model, zero-order infusion.
Perhaps a directory should be created for MathCad files in the Stanford PK/PD repository.
Director, Biopharmaceutics, Biovail Corporation International, Contract Research Division, 460 Comstock Road,Toronto, Ontario, Canada M1L 4S4
On 5 Dec 1995 at 11:05:37
PharmPK mailing list recipients:

In response to the e-mail from Dr. Ganes, I have set up a directory for PK/PD files for
MathCad in the repository I maintain at Stanford. To send files, connect using anonymous
FTP to pkpd.icon.palo-alto.med.va.gov, and log into the directory "newfiles.dir". You will
have read/write permission in that directory. Download your files to that directory, and
35
send me an e-mail about what you have downloaded. I will transfer them to the MathCad
directory.
Thanks in advance for making your PK/PD software publicly available.
Steve Shafer
36
S EC T I O N 12
Phenytoin Dosed by Total or Lean Body

Weight
On 8 Feb 1995
One of the pharmacists asked this tonight...

Should IV Dilantin be dosed on a total body weight or a lean body weight?
He said he had attended a seminar and had this data somewhere, but couldn't find it in any
of our sources at work.
Leo Horishny
On 8 Feb 1995
The questions of dosing phenytoin based on IBW or TBW is still somewhat in questions.
I refer you to a reference (de Oca GM, Gums JG, Robinson JD. Phenytoin dosing in obese
patients: Two case reports. Drug Intelligence and Clinical Pharmacy 1988; 22: 708-10.)
that may help. In essence the author state that dose needs to be adjusted in obese patients because they have large volumes of distribution. They quote Abernathy and Greenblatt (Abernathy DR, Greenblatt DJ. Phenytoin disposition in obesity. 1985 Archives of Neurology, 42 468-71.) that a dosing weight is equivalent to IBW + [1.33(TBW-IBW)]. In my
experience, IBW under doses obese patients and does not result in therapeutic serum
phenytoin concentrations. I would suggest that using serum phenytoin concentrations to
adjust dosing would definitely be necessary in these patients combined with a non-linear
bayesian dosing program to achieve early therapeutic serum concentrations.
Michael Burton
On 8 Feb 1995
I agree in my experience the use of a nutritional weight that is some where between the
IBW and the ABW results in a better estimate of the actual Vd of an obese patient. I use
ABW + (1.2(ABW-IBW)). You can also use this approach to help adjust the dosage in preg37
nant patients as their volume of distribution changes throughout the gestation period. If
the mother was at steady state prior to the pregnancy, you can adjust the dose using prepregnant weight and current weight instead of ABW and IBW.
Carol Boyes
On 11 Feb 1995
Several people responded to the query, "Should IV Dilantin be dosed on Lean

Body Weight versus Total Body Weight?"
Two formulae were presented:
Dose=IBW+[1.33(TBW-IBW)]
Arch. of Neur., 1985, 42, 468-71
Dose=ABW+[1.2(ABW-IBW)]
C. Boyes R.Ph.
Both these formulae calculated give answers GREATER than the TOTAL body weight
For Example:
IBW = 70kg
Dose = 70kg+[1.33(120kg-70kg)]
D
TBW= 120kg
= 70kg+[1.22(120kg-70kg)]
Dose = 70kg+[1.33(50kg)]
D
= 70kg+[1.22(50kg)]
Dose = 70kg+[66.5kg]
D
= 70kg+[61kg]
Dose = 136.5kg
D
= 131kg
Ought not the calculation be:

D = 70kg+[0.33(120kg-70kg)]
D = 70kg+[0.33(50kg)]
38
D = 70kg+[16.5kg]
D = 86.5kg
0.33 is what is used at Bethesda North. This was oered by Michelle Svinte, PharmD and
Andrew Lantz, RPh
Leo Horishny
On 13 Feb 1995
I suspect that if you use IBW + [0.33(TBW-IBW)] or IBW + [0.2(TBW-IBW)] that this
will give the correct dosing weight. We use this scheme for aminoglycosides and it works.
Michael Burton
On 17 Feb 1995
Thanks for the compliment. I'm not sure I'm an "authority" but I have reviewed the literature extensively and work with lots of epilepsy patients. The formula by Abernethy is
the only proposed formula out there, that I know of, for dosing phenytoin in obese individuals. If I understand some of the message, you are concerned that it calculates a BW
higher than the patient's original weight--that's correct. In fact, Abernethy states that the
Vd in obese individuals may be higher. Personally, I do not have direct clinical experience
with using this formula in obese patients. When used, the doses calculated are oftentimes
"enormous". My suggestion has usually been to 1) use the formula to calculate a dose then
2) give a dose that all are comfortable with (based on experience and the condition of the
patient). Sometimes this is about 1/2 of the calculated dose. Once the dose is administered, then re-assess the patient and perhaps obtain a serum concentration. If the patient
is still seizing, you can then administer the other 1/2 of the calculated loading dose. In
other words--the formula is probably correct, but clinicians haven't readily accepted the
doses needed, therefore clinical judgement must be used.
Hope this "non-answer" helps.
This comment is from Nina Graves at U. of Minnesota. She has more experience with
phenytoin dosing than me so I asked if she would agree with the formula for dose weight
39
of phenytoin in obesity: dose weight = IBW [1.33(ABW-IBW)] as proposed in Arch Neur

1985, 42. 468-71
Keep in mind that all drugs do not distribute like aminoglycosides. Phenytoin is apparently highly lipophilic, unlike aminoglycosides.
David Axt1
40
S EC T I O N 13
pKa for ketoconazole

On 1 Nov 1995 at 22:34:22
There are a young graduate student doing a research on extraction of ketoconazole (Nizoral) from soap, to estimate aging and caducity date for a pharmacological development of
ketoconazole.
Chemical Abstracts is not available locally. None of our sources of information have this
data. Lange's Handbook of Chemistry was the only book with info related... but not for
ketoconazole.
She needs, specifically, the value of pKa for ketoconazole in acid and basic medium, the 2fase binomial distribution for extraction or any technique related to determine both values...
Carlos Alberto Sanchez Velasco
Centro de Informacion y Documentacion para la Docencia y la Investigacion, Universidad
Veracruzana,Xalapa, Veracruz, MEXICO
On 3 Nov 1995 at 10:00:36

There are a young graduate student doing a research on extraction of
ketoconazole (Nizoral) from soap, to estimate aging and caducity date
for a pharmacological development of ketoconazole.
Carlos: Dr. Mann and I studied the dissolution of keto in this article: 9. Carlson JA, Mann
HJ, Canafax DM. Eect of pH on ketoconazole disintegration and dissolution. Am J Hosp
Pharm 1983; 40:1334-1336. We use a very basic spectrophotometric assay for this study.
Hope it helps you.
Daniel M Canafax
41
S EC T I O N 14
PKPD Wheal Flare

On 24 Feb 1995
I am interested in a PKPD link between adult antihistamine pk/wheal & flare to pediatrics. I understand that the wheal and flare is not validated for antihistamines. Does anyone have any experience here?
Brad Gillespie
On 25 Feb 1995
My experience of people who make unsupported assertions such as 'x is not validated for
y' is that I have diculty understanding the problem. There have been published accounts
of PKPD models for antihistamines which describe wheal and flare responses in relation
to plasma concs via eect cpt models (of the top of my head I cannot cite you a reference
but can do so when I get back to work on Monday). But the issue is what is your real problem? What are you wanting to do with any models of PKPD links for antihistamine wheal
and flare? What is the pediatric angle? What on earth does 'validation' mean to YOU?
Nick Holford
On 27 Feb 1995
Have you looked at any indirect PK/PD models for this? Perhaps some work in this area
may be of use to you. And I quite agree with what Dr. Holford said! In this work, you just
have to go ahead and try it, and see if the results are useful or not. That's about as close to
'validation' as it gets, I think. ;-)
Diane Mould
42
On 27 Feb 1995
If I may I would suggest that you contact Dr. Keith Simons, Professor, Faculty of Pharmacy, U of Manitoba, Winnipeg, CAD. He and his wife, Estelle, are experts in the area of
antihistamine kinetics and their study in peds..... They may be able to help you.
Jim Axelson
43
S EC T I O N 15
Propofol Pharmacokinetics
On 26 Apr 95
Could someone give me a number for the SERUM level of Propofol that would be
achieved during a prolonged (>6 hours @ 30micrograms/kilogram b.w.) infusion of Propofol in an ICU setting?
Narayan Baliga
On 27 Apr 95
I have an un-referenced statement that the clearance of propofol is 104 L/h (in a 70 kg person?). The terminal t1/2 (3 cpt model) is said to be 4 h but distribution half-lives of about
0.5 h are probably the main determinant of the conc at 6 h.
The question does not specify the infusion rate clearly. I assume that the rate is 30 mcg/
kg/h and not a total dose of 30 mcg/kg over 6 h.
So assuming steady state at 6 h the predicted conc is
Css = Rate In/Clearance = 30 ug/kg/h * 70 kg / 104 l/h = 20 ug/L
Nick Holford
On 27 Apr 95
Thank you Nick. The rate we use is 30 micrograms/kg/minute not per hour. Also I was
after the plasma level of propofol. I understand a large portion of propofol enters the red
cells but I could not get a reference on the actual proportion of redcell-bound : proteinbound : free in plasma during a steady state.
Narayan Baliga
44
On 28 Apr 95
OK. I suspect the clearance I quoted of 104 L/h is for plasma (blood CL would be very unlikely at that value). So you can use it to predict plasma propofol. Given the rate of 30 ug/
kg/min that would predict a conc of about 1200 ug/L or 1.2 mg/L. Does that sound correct?
Nick Holford
On 5 May 95
The pharmacokinetics of propofol are best described by a multicompartmental model.

Thus, calculations based on clearance and Vdss are not likely to be helpful, except as
steady state is approached. I would agree with Nick's assumption that by 6 hours steady
state will be approximated, although the half-life in ICU studies is in the area of 2-4 days.
The pharmacokinetics of propofol are also likely to be moderately nonlinear, as propofol's
clearance exceeds liver blood flow, and propofol decreases cardiac output and liver blood
flow in a concentration dependent manner. Nonlinearity of propofol pharmacokinetics
have been demonstrated in dogs, but not in human studies to date.
I would suggest downloading a simulation program, which you can use to predict the propofol concentrations from any arbitrary drug infusion regimen. You can find three such
programs, STANPUMP, STELPUMP, and IVA-SIM on my software repository, available
via WWW page at URL:
http://pkpd.icon.palo-alto.med.va.gov
There are a variety of propofol pharmacokinetic published. STANPUMP contains
specific ICU pharmacokinetics, based on high-resolution PK studies performed here at
Stanford. I would guess there is more to your question than just wanting an estimate of
plasma propofol concentration, and please feel free to contact me at the e-mail address below for additional questions.
I haven't been able to identify any reference of the RBC:plasma partition coecient for
propofol, but Zeneca has studied this. They tell me that unpublished studies performed
internally show a partition ratio of 1:1.
Steve Shafer
45
S EC T I O N 16
Rat/Mouse Blood Flow

On 21 Feb 1995
I am interested in books or references about blood flux through the kidneys of male and
female mouse. (Not rat Wistar). If you know it or where I can find it.
Ignacio Segarra
On 21 Feb 1995
Here are a couple of references which list the blood flow through the major organs of
mouse.(Not given separately for male and female mouse)
1. Leonard E. Gerlowski and Rakesh K. Jain 1983 J.Pharm. Sci., 72, 1103.
2. Brian Davies and Tim Morris 1993 Pharmaceutical Research, 10, 1093.
Brinda Koneru
On 21 Feb 1995
A good reference that deals with blood flow, organ weights and volumes as well as other important physiological parameters in a number of species, is that by B. Davies and T. Morris
1993 Pharm. Res., 10, No. 7, 1093-1095. Renal blood flow in the mouse (0.02kg) is cited as
1.3 mL/min. Two references for parameters in the mouse are cited.
Ron Sawchuk
On 2 Mar 95
I am constructing a large-scale PBPK model of inhalation of gaseous toxicants by rats and

mice. I have found references that give values of organ weights (for most organs) as fractions of body weight (done by careful dissection) and blood flow rates through these or46
gans (by radioactive microspheres) for rats. Does anyone know of similar compilations for
the mouse? Thanks for your assistance.
Michael C. Kohn
On 3 Mar 95
The organ weights and tissue perfusion rates for Sprague-Dawley rats can be found in
M.D. Delp et al. 1991 Am. J. Physiol., 261, H1487--1493. Another source is W.L. Roth et al.
1993 Risk Analysis, 13, 531--543
Ron Sawchuk
47
S EC T I O N 17
Reversible Metabolic Systems

On 11 Jan 1995
In a paper by Cheng and Jusko (Pharm. Res. (1990), 10, 1003-1010) the method for calculation of distribution clearance in a reversible metabolic system is presented. Equation 38
page 1005 needs C'(0), the first derivative of C(t) at time 0. How is this first derivative obtained. Can anyone provide an equation, method or reference for the calculation of
C'(0).
How are the equations for the calculation of the parameters of this model aected if there
is chemical interconversion, not enzymic, in both the central compartment and peripheral
spaces.
On 12 Jan 1995
a) C'(0) is usually assumed to be 0 before the drug is administered :-)

b) Enzymes are chemicals. Makes no dierence to the model. You just need to put in a suitable model element to account for the conversion e.g. to a separate compartment.
Nick Holford
48
S EC T I O N 18
Search for Compendium of Cytochrome P450

drug interactions
On 3 Nov 1995 at 10:00:34
Is there a compendium available of cytochrome P450 isoenzyme interactions with various

drugs? Is there one that is in progress ? There are many articles in this growing field, but
I am looking for a complete, but simple table that lists drugs and P450 isoenzyme interactions (ie inhibit, enhance, induce, etc).
J Paul
On 3 Nov 1995 at 15:58:52
There is a list by S. Saklad, Pharm.D. at http://saklad.uthscsa.edu/CYP_and_Drugs.html,

which he apparently took from: Antidepressants and Cytochrome P450 Enzyme Involvement (DeVane CL. J Clin Psychiatry 1994;55[12 Suppl]:38-45.
I have heard that there is a table in a recent '95 Clinical Pharmacokinetics article by
Preskorn and Magnus: I haven't been able to get the complete citation yet, but if anyone
else knows I'm interested too.
Bill Budris
49
S EC T I O N 19
Single-dose Aminoglycoside Therapy

On 22 Jun 1995 17:18:55
Do any of the pharmacy practitioners on this list work at institutions which dose IV aminoglycosides on a q24h basis? If so, please describe your experience with this regimen.
Paul Trusten, R.Ph.
VA Medical Center, Northampton MA
On 22 Jun 1995 16:15:44
We've been dosing aminoglosides on a 'q24h' basis for a year or so with excellent results.
Of course, some patients are on an even longer frequency (i.e. q48h) when their renal function dictates.
Many patients are dosed with a single 10 hour 'random' level after the initial load. I have
encouraged practitioners to obtain a peak and a level at approx 2-3 x the anticipated t1/2
when there is significant doubt that the patient will fall into the category of 'normal'. By
doing so, you have all the information you need to calculate the volume of distribution and
clearance. Then, if necessary, you have what you need to design a rational dosing regimen
if the levels don't come out the way you wanted them to.
We have had no cases of aminoglycoside related nephrotoxicity using this approach, so far.
Neil Sandow
On 22 Jun 1995 20:19:24
Yes we use single dose gentamicin when ever we can (mainly for convience and cost control) if peak and trough predictions warrant. In the main it seems to work just as well as
q12 or q8h dosing.
Ben Holland
50
On 23 Jun 1995 19:24:45

Do any of the pharmacy practitioners on this list work at institutions which dose IV
aminoglycosides on a q24h basis? If so, please describe your experience with this regimen.
Take a look at the June edition of Brit J Clin Pharmacol for some NZ experience from
Evan Begg.
Nick Holford
Dept Pharmacology & Clinical Pharmacology, University of Auckland, Private Bag
On Fri, 23 Jun 1995 08:35:55
An excellent review article is "Once-daily administration of aminoglycosides" in Annals of

Pharmacotherapy 1994 June 28(6):757-66.
Catherine Heyneman, Pharm.D.
Idaho State University College of Pharmacy, Drug Information Service
On 23 Jun 1995 14:20:22
We estimate the initial daily dose based on severity of infection (mild: maximum dose 3
mg/kg/d; moderate: 4.5 mg/kg/d; severe: 6 mg/kg/d). The daily dose is then modified
based on estimated CrCl. Patients with estimated CrCl <50 are generally dosed oncedaily. Those with CrCl >50 are dosed q 12h OR q 24h depending on the clinical situation
and/or comfort level of pharmacist, physician, etc.
When using q24h dosing as above, we are primarily interested in achieving a desired
AUC, and secondarily a high peak level. We use a single 5 hr post-dose value to estimate
AUC- later time points seem to vary too much depending in Ke. Target value: 3 mg/L for
"mild"; 4.5 mg/L for "moderate"; 6 mg/L for "severe" (ironically, the same numbers as maximum doses listed above).
As I alluded above, we don't use q 24h in all patients: most commonly, it is used in ICU patients, home care patients, and patients with UTI +/- bacteremia. One must be cautious
in reporting nephrotoxicity rates, as nephrotoxicity will be low regardless of dosing
method if the duration of therapy averages < 4 days.
51
Steve Ebert
On Sat, 24 Jun 1995 09:21:52

We've been dosing aminoglosides on a 'q24h' basis for a year or so with excellent results. Of course, some patients are on an even longer frequency (i.e. q48h) when
their renal function dictates.
Many patients are dosed with a single 10 hour 'random' level after the initial load. I
have encouraged practitioners to obtain a peak and a level at approx 2-3 x the anticipated t1/2 when there is significant doubt that the patient will fall into the category of 'normal'. By doing so, you have all the information you need to calculate the
volume of distribution and clearance.
Then, if necessary, you have what you need to design a rational dosing regimen if the
levels don't come out the way you wanted them to.
We have had no cases of aminoglycoside related nephrotoxicity using
far.
this approach, so
We, too have been using once-daily dosing for about a year, although the only MD's that
seem to use it are Infectious disease people. It is not yet in common usage. A couple of
follow-up quesions.
What information does a random 10 hour level give you, and what adjustments do you
make based on that?
What peak and trough levels do you aim for? Are you concerned about ototoxicity with
higher peaks. Do you routinely do audiometry in these patients?
How do you initially dose the patient, empirically? Ie., 5mg/kg/day or something else?
What "loading dose" vs. "maintainence dose do you use? Our MD's just use the 5mg/kg/
day dose, without a load. How do you adjust for patient's with elevated creatinine?
Lastly, do you use this approach in immunocompromised patients? Does the postantibiotic eect which accounts for the ecacy and logic of this approach also hold true
for the immunocompromised patient?
We too, have not seen an increase in cases of nephrotoxicity that can be attributed to therapy, but that may change as more cases are reviewed in the literature.
Nathan Pruitt
52
On 27 Jun 1995 22:17:37

We, too have been using once-daily dosing for about a year, although the only MD's
that seem to use it are Infectious disease people. It is not yet in common usage.
couple of follow-up quesions.
What information does a random 10 hour level give you, and what adjustments do you
make based on that?
If you use the (shudder) nomogram supplied by Harford(?) and the 10 hour level falls below the toxic line, then it is assumed that the risks of nephrotoxicity with q24h dosing are
minimal.
What peak and trough levels do you aim for? Are you concerned about ototoxicity with
higher peaks. Do you routinely do audiometry in these patients?
With this approach we aim for peaks ~15-20 and 8-12 hours below 2 mcg/ml.
How do you initially dose the patient, empirically? Ie., 5mg/kg/day or something
else? What "loading dose" vs. "maintainence dose do you use? Our MD's just use the
5mg/kg/day dose, without a load. How do you adjust for patient's with elevated creatinine?
Yes, 5mg/kg/day will do it for patients close to their ideal body weights. No need for a
larger loading dose since levels fall so low before each dose, accumulation is minimal.
When the creatinine is elevated or the patient otherwise is problematic we will often
draw serial levels to enable us to dose with better precision.
Lastly, do you use this approach in immunocompromised patients?
Does the postantibiotic effect which accounts for the efficacy and logic of this approach also hold
true for the immunocompromised patient?
No, probably not. In these patients we generally don't trust the post-antibiotic eect. We
tend to dose these patients with greater frequency.
Neil Sandow, Pharm.D.
Brookside Hospital, San Pablo, CA
On 28 Jun 1995 08:19:58
As a newcomer to the "group" I apologise for joining the conversation at a late stage. I assume the dialogue is concerning gentamicin.
We also discussed the possibility of introducing once daily dosing for neutropenic patients, but felt there was little evidence to support this and have continued to use 8-12
hour dosing schedules.
53
In Glasgow, a nomogram has been developed using data from a NONMEM analysis and
the population data have also been incorporated into a Bayesian algorithm for dosage
modification.
Duncan Jodrell
Edinburgh University.
On 28 Jun 95 09:37:26
There are several studies of once daily dosing in neutopenic patients: J Drug Dev
1988;1(Suppl 3):119-124. Ann Intern Med 1993;119:584-593. (The EROTC study of 677 patients). J Antimicrob Chemother 1978;4S:85-101 We use extended interval dosing in neutropenic patients, but switch to traditional dosing methods when the infection is not responding and the 8-12hr drug level is undetectable (particularly if gentamicin is the only gramnegative coverage). We designed nomogram similar to Nicolau's at Hartford, but use a
5mg/kg dose.
A complete list of citations is available on my homepage: http://osler.wustl.edu/~reichley/
Richard Reichley
Clinical Pharmacist, Pharmacokinetics, Barnes and Jewish Hospitals at Washington University Medical Center, St. Louis, MO 63110
On 30 Jun 1995 23:22:38
We are now routinely using q24h dosing. Doses are 5mg/kg for patients predicted to have
a "normal" Vd and 7.5 mg/kg for large Vd. We measure only a 12 hour level and try to keep
it <3 mcg/ml, however, I sometimes will increase the dose if it is < 1 mcg/ml. In about 80
patients we have not identified any dose related treatment failures, or nephrotoxicity.
Costs are also less due to less frequent dosing, and fewer serum levels measured.
Carl Heisel, RPh.
Emanuel Hospital, Portland
54
S EC T I O N 20
Urinary excretion rate to plasma concentrations

On 12 Dec 1995 at 16:23:06
Dear Colleagues
I would like some opinions from members of the group on the practice of determining
plasma concentrations of a drug from urinary excretion data. I have recently come across
this method in a paper and wondered how accurate or valid data (eg t1/2, z) based on this
method actually are. In addition, I also know the drug undergoes active renal excretion.
The method is used when plasma concentrations fall below the limit of quantitation and
the urinary excretion rate for the drug is used to determine plasma concentrations situated in the middle of the collection interval by dividing the excretion rate in the interval
(dAe/dt) by the renal clearance calculated from when plasma levels could be determined
(CLR 0-x hr).
I thank you in advance for your assistance.
Dave Boulton
School of Pharmacy, University of Otago, P.O. Box 913, Dunedin, New Zealand
On 13 Dec 1995 at 14:09:29
Urine PK analyses are better than nothing and can provide useful estimates of K and,
therefore, half-life. The absolute bioavailability (F) can be obtained if the drug is excreted
totally unchanged, or provided all metabolites are identified, are known to be excreted in
urine, and all can be measured (often easier said than done). Renal clearance can be calculated by dividing the total amount excreted unchanged during a urine collection interval
by the plasma during that interval, although it is better to have urine collections and AUC
to infinity.
Clearance (systemic) and volume of distribution cannot be obtained from urine data alone.
55
In switching from plasma to urine one has to ensure of course that, assay performance is
adequate and comparable in both biological fluids.
The major problem occurs with drugs of very short ( say <1 hr) and very long half-life (>
24 hr) -- The former makes it dicult to get enough data, while the latter is susceptible to
problems from missed samplings since all urine should be taken over several days. Furthermore, unless the pre-terminal (distribution) phases are inordinately long then it is unlikely
that subjects can pass a sucient number of urine samples to capture this part of the PK
profile. This also occurs for non-intravenous administration in that the absorption phase is
often so rapid that no more than 1 or 2 samples of urine can be collected even when subjects are "pre-hydrated" before dosing (which in itself can be problematical, e.g. with oral
administration of solid dosage forms).
Nonetheless, urine measurements can provide useful data for PK. For example, we recently used urinary excretion data to study the mechanism of absorption of amoxycillin
(see : Eur J Pharm Biopharm 40,374-378,1994; Br J Clin Pharmac 38,274-277,1994). Hope this
is of some help.
Bruce Charles
Pharmacy Department, Univ. Queensland, Brisbane, Australia.
On 13 Dec 1995 at 14:09:33
The validity of this depends on the constancy of renal clearance and the quality of the
urine excretion data. This is one method that can be used to check for long terminal halflives which are not evident from the plasma data, provided the two criteria mentioned
above are fulfilled.
Leon Aarons
Pharmacy Department, University of Manchester, Manchester, M13 9PL, U.K.
56
On 14 Dec 1995 at 10:14:13
Dear Dave,
A good deal of our research involves following the excretion rates of drugs because we do
not have the facilities for taking blood samples from human volunteers. The assumption
that must be met for urinary analysis is that drug is excreted from the central compartment by a definable process, usually first order. The other consideration is that you will
only get information on the fate of that portion of the parent compound that is analyzed
in urine; ie - analysis of a metabolite will only give information on that fraction of the dose
that is excreted as the metabolite.
Set up your spreadsheet with columns for time, midpoint, volume, and concentration.
Time is the time since the dose was taken. midpoint is the center of the sampling interval
(sample at 1 and 2 hours; the midpoint for the 2 hour sample is 1.5 hours). Volume is the
TOTAL urinary output since the last sample; your subjects must give you virtually every
drop they produce from time 0 to the end of the sampling period (12 hours, 24, 36 ... just
have to measure it to know for sure). Concentration is determined in the normal manner
by HPLC or whatever instrument you use.
CALCULATIONS:
1. mg recovered = concentration * volume
2. urinary clearance = dU/dt= (mg recovered)/(sampling interval)
Some spreadsheets can't handle subtracting a cell from the next one in the column.
In that case, dudt=mg_recov/(2*(time-midpoint))
Under ideal conditions, a plot of urinary clearance vs. midpoint will exactly parallel plasma
concentration (with an arbitrary scaling factor). We have used this fact in the formulation
of several bioequivalent products under the assumption that if two formulations are bioequivalent, then they should be excreted in a bioequivalent manner. Urinary clearance gives
you a non-invasive tool 0th early formulation work for bioequivalence; you switch to
blood when you're close.
Urinary clearance is especially powerful when combined with a deconvolution program
such as PCDCON by Bill Gillespie. Using dUdt as the input function and Ke (either from
literature or from clearance by subjects taking an immediate release dose of the drug un57
der investigation) as the impulse response, you can get both the cumulative input of drug
into the previous compartment and the rate of input.
NOTE: I said previous compartment. If you are measuring a drug that is excreted intact,
then the input calculated by deconvolution is input into the central compartment. If you
are measuring a metabolite, then you are measuring the input of drug from the central
compartment into the metabolizing organ/enzymatic system. So with intact drug, you are
measuring ka. If the drug is in an SR or CR formulation and you assume that absorbance
is much faster than dissolution, then the input rate from deconvolution is the in vivo dissolution rate.
I hope that this will help you decide whether to use urinary clearance or not. If you have
any further questions, e-mail directly.
Kris Holt
Graduate Research Assistant, Oregon State University
On 15 Dec 1995 at 16:17:42
Dear Leon
Thanks for your comprehensive reply to my query regarding conversion of urinary excretion rate to plasma concentrations. I must admit I initially thought this practice would be
a little suspect for quality quantitative work but the responses I have recieved have
changed my mind and I see that the technique is useful in quite a number of situations.
Thanks again.
Dave Boulton
School of Pharmacy, University of Otago, P.O. Box 913, Dunedin, New Zealand
58
3
1996
59
S EC T I O N 1
Accumulation ratio calculation

On 30 Oct 1996 at 23:05:44
I would appreciate if any members of PharmPK can advise me on what should be a very
simple question on how to calculate accumulation ratio (AR).
Drugs were administered either once (QD) daily or twice daily (BID) for 8 consecutive
days. AUC0-dosing interval and AUC 0-infinity are available for both days 1 and 8 on QD
and BID.
Is AR:
1. AUC0-dosing interval day8/AUC0-dosing interval day1
2. AUC0-infinity day8/AUC0-infinity day1
3. AUC0-dosing interval day8/AUC0-infinity day1
All three ways have been suggested but there must be one correct way of calculating AR
many thanks in advance
Faruq H Noormohamed
Department of Therapeutics, Chelsea and Westminster Hospital, 369 Fulham Road, LONDON SW10 9NH
On 31 Oct 1996 at 12:28:07

Is AR:
1. AUC0-dosing interval day8/AUC0-dosing interval day1
This fits closest to my own definition of AR which is the ratio of the conc at SS (or after
N doses) to the conc after the first dose at the same time after the dose e.g. the ratio of
the trough conc at SS to the conc immediately before the second dose. Using the AUC
60
gives some kind of time averaged conc on day 8 divided by the conc averaged over the
same period after the first dose.
2. AUC0-infinity day8/AUC0-infinity day1
No. Doesn't fit my definition of AR.

3. AUC0-dosing interval day8/AUC0-infinity day1
No. This ratio should be <= 1 (approaches 1 as steady state is reached). The AR should always be > 1.
-Nick Holford,
Dept Pharmacology & Clinical Pharmacology, University of Auckland, Private Bag 92019,,
Auckland, New Zealand
http://www.phm.auckland.ac.nz/Sta/NHolford/nholford.html
On 31 Oct 1996 at 12:28:28,
Faruq:
There is no unique definition of the accumulation ratio (AR), so there is no *correct* way
of its calculating. In Gibaldi & Perrier (2nd edition) you will find 3 versions of AR:
1. AR = C_ss_min/C_1_min,
where the subscript min corresponds to the plasma concentration immediately before the
dose intake. If the dose is administered in the post-absorptive, post-distributive phase this
definition of AR will result in a well-known equation:
AR = 1/(1 - exp(-lambda_z*tau)) (1)
2. AR = C_ss_max/C_1_max,
where the subscript max indicates that the peak concentration is used in calculating AR. If
the drug kinetics can be described by the one-compartment model you will get again Equation (1).
3. AR = C_ss_av/C_1_av,
61
where average concentrations at steady state and during the first dose are used. The latter
definition is the most common since it results in a simple non-compartmental formula,
and is, therefore, the most appropriate:
AR = AUC_ss_tau/AUC_1_tau
Thus, in you three formulas:
1. AUC0-dosing interval day 8/AUC0-dosing interval day 1
2. AUC0-infinity day 8/AUC0-infinity day 1
3. AUC0-dosing interval day 8/AUC0-infinity day 1
the first one is consistent with the latter definition. However, to get an unbiased estimate,
steady state should be achieved at day 8, otherwise you will under-estimate AR.
By the way, if you have steady state at day 8, your third formula will give unity if the kinetics of your drug is linear and time-invariant. If there is auto-induction the ratio will be
lower than one. In the case of auto-inhibition it will be higher than one. So, this ratio is of
importance, too.
Vladimir Piotrovskij, Ph.D. , Janssen Research Foundation, Clinical Pharmacokinetics, B2340 Beerse, Belgium
On 31 Oct 1996 at 12:29:32
Faruq:
By a definition, the AR (or often referred to as "fraction of the steady state, achieved in
the K-th period of the dosing schedule" is calculated as the ratio between the AUC in the
K-th period and the AUC in a period at steady state. As AUC in a period at steady state is
equal to the AUC to infinity after the first dosing, obviously the correct way is number 3.
Ivan Nestorov, PhD
62
S EC T I O N 2
Albumin in TPN
On 19 Nov 1996 at 17:08:16
We currently have two small (2.33kg and 3.88kg) children in our PICU.
Both were premature but with no pulmonary complications. They came in with cases of
RSV which subsequently led to ARDS. They were very sick puppies from the start.
We started giving them parenteral nutrition early on. Initially the feeding was conservative and now, because of lower TP and Albumin levels, the docs have decided to get aggressive. Both are currently on High Frequency Oscillation Vents, and sedated. One is also on
Vecuronium. Not good candidates for enteral feeds.
The attendings want to add Albumin to the TPN to increase serum levels. There is no
sign of hepatic dysfunction or acute renal failure so I can only surmise that the lowered TP
and Albumin levels are due to malnutrition. My argument was to increase glucose and protein and the TP and Albumin would follow shortly after.
A second reason for wanting Albumin was to increase oncotic pressure?? I believe that
there are other ways to do this that are less expensive and more eective.
Does anyone have any data to support or dismiss the addition of Albumin to TPNs for the
purpose of increasing serum levels. Are there any studies of the kinetics involved in the absorption and distribution of Albumin in neonates. Is the addition of lipids to the mix going to promote the distribution of Albumin as one attending contends?
This is a recuring argument. I need the literature to either convince me or the docs once
and for all. I am also doing a med-line search to augment any information that you may
have.
Please, anecdotal accounts are also welcomed.
Robert G. Aucoin RPh
Peds Clinical Pharmacist, OLOL RMC, Baton Rouge, LA
63
On 20 Nov 1996 at 12:02:28
Robert
From my basic science perspective, both you and the physicians have good points. Malnutrition seems the likely explanation for the hypoproteinemia, and unless there is an undetected hepatic problem, increased parenteral glucose and amino acids should solve it. But
this process may be too slow or there may be a defect in hepatic albumin secretion as a
consequence of the infants' prematurity. Especially if the patients are showing signs of
edema, the priming dose of albumin sounds like a good idea assuming there are no
immune-system consequences in response to i.v. albumin.
Combining your proposal with the physicians' proposal will result in a sort of primed infusion of albumin with the priming dose consisting of albumin itself and the infusion consisting of its biosynthetic precursors.
If the plan is to infuse albumin i.v., absorption should not be an issue, and distribution
should be as it normally is for hepatocellular-secreted albumin. If the parenteral route is
not i.v., then addition of albumin could be detrimental since it will increase extravascular
oncotic pressure and actually promote edema.
You are of course correct that there are other ways to increase oncotic pressure, but
albumin is certainly the way evolution solved the problem.
I'm unsure I understand the point you make about adding lipids to the mix and the consequences for albumin distribution. Distribution should not be an issue if the parenteral
route is i.v.
Robert D Phair PhD
BioInformatics Services: http://www.webcom.com/rphair
64
On 20 Nov 1996 at 16:04:17
Bob,
There is rarely a second reason for giving iv albumin. The main reason and often the only
one is to increase plasma oncotic pressure. Thus, the short answer to your question is that
in the absence of fluid / hemodynamic problems, there is no rational for exogenous albumin. The best way to elevate plasma albumin is support hepatic protein production
through good nutrition.
N. Anaizi, PhD RPh
Univ of Rochester Med. Center
On 22 Nov 1996 at 11:50:01
This isn't my area so I won't even pretend I have any of the answers. I'm the clinical specialist for a spinal cord injury unit. On the few occasions when we do use albumin it will
only maintain oncotic pressure for a short period of time, right? Isn't this because extrinsic albumin has a very short half-life? Anyway, I have passed this message to a collegue in
Orlando Florida who is a peds. specialist like yourself. Hopefully, he will be able to respond.
Tom Mobley
On 25 Nov 1996 at 10:07:53

The attendings want to add Albumin to the TPN to increase serum levels. There is no
sign of hepatic dysfunction or acute renal failure so I can only surmise that the lowered TP and Albumin levels are due to malnutrition.
Not necessarily. Premies and term neonates are hypoalbuminemic, relative to older kids.
And if these two have active ARDS, lung capillaries are leakier to albumin.
My argument was to increase glucose and protein and the TP and Albumin would follow
shortly after.
Agree, to the point that you have to provide enough amino acid substrate to prevent albumin from being scavenged as an energy/protein source.
A second reason for wanting Albunin was to increase oncotic pressure?? I believe that
there are other ways to do this that are less expensive and more effective.
65
Can't think of anything else except mannitol or hypertonic saline, neither one of which
seems like a good idea to me. Do the neonatologists want to increase oncotic pressure to
supernormal or simply give the kids pressure they would otherwise have? If the former, is
that a treatment modality for ARDS? If the latter, better to do it before they become edematous.
Does anyone have any data to support or dismiss the addition of Albumin to TPNs for
the purpose of increasing serum levels.
Can't say for neonates. Our adult patients on TPN are, however, always hypoalbuminemic, and they don't catch up very quickly on TPN alone.
Is the addition of lipids to the mix going to promote the distribution of Albumin as
one attending contends?
Have never heard of this. I'd be interested in learning the mechanism, if it's true.
Wouldn't be why I'd use lipids, anyway.
Randy Trinkle, BScPharm, BA
Dept. of Pharmacy, Dawson Creek & District Hospital, Dawson Creek, BC
66
S EC T I O N 3
Aminoglycoside - daily dosing

On 6 May 1996 at 8:17:00
I am a hospital pharmacist, and recently we have been receiving orders for high doses of
aminoglycosides to be used once daily. Both gentimicin and tobramycin. Doses range
from 250mg to 300 mg given once daily.
Doyle Wilkinson, R. Ph.
Doctor's Regional Hospital
On 7 May 1996 at 11:18:01
Doyle
I was at the National Pediatric Infectious Disease Conference last month in New Orleans, LA, and mention was made of once a day dosing of aminoglycosides. Docs there expect to see this in their hospital in the near future. There is also literature around verifying the use on once daily dosing. It seems the logic behind all of this is that a high peak is
not the problem with aminoglycosides, its the sustained trough. I don't have the literature
references at home but I will get what I can and post it to the group. There have been several questions on medical list concerning this lately with no good reply that I have seen. I
don't presume to oer the perfect or even best response. I only hope to stimulate a little
conversation and learn something in the process.
Robert Aucoin RPh
Peds Clinical Pharmacist, Baton Rouge, LA
On 8 May 1996 at 10:40:51
We do this routinely at my institution and it is a popular topic when I do CE programs.

For a recent article, look for a meta-analysis by Michael Barza in a recent issue of Lancet
67
(I'm pretty sure it was within the last month or so). Their conclusion was that "...[oncedaily] aminoglycosides in patients without pre-existing renal impairment is as eective as
multiple daily dosing, has a lower risk of nephrotoxicity, and no greater risk of ototoxicity.
Given the additional convenience and reduced cost, once daily dosing should be the preferred mode of administration."
Gary D. Theilman, Pharm.D.
Assistant Professor, Dept of Clinical Pharmacy Practice, School of Pharmacy, University
of Mississippi
http://fiona.umsmed.edu/~theilman
68
S EC T I O N 4
Aminoglycosides Consensus Document

On 7 Oct 1996 at 11:11:51
Dear Colleague,
You may recall that a few months ago, the PharmPK list initiated a parallel avenue for a
more organized, purposeful discussion whose ultimate aim is to integrate our "collective
wisdom" on specific topics in "consensus documents". The process begins with a coordinator preparing an initial document, which is then posted for the group to read and critique.
Feedback should be directed to the coordinator, who will then revise the initial document
as necessary. The final product will then be published as a document reflecting our consensus on the topic.
We have chosen three topics of current clinical interest:
1.
) Vancomycin kinetics and monitoring.
2. ) Administration of Beta-Lactams (intermittent vs cont. inf.).

3.
) Once-daily aminoglycoside dosing.
I was selected as the coordinator for the 3rd topic. I have completed the initial document.
Dr. David Bourne has now posted it on the web site. You may find it in the following page:
http://www.pharmpk.com/consensus/odacd.html
Please take the time to read it, and give me your feedback
Thanks
N. Anaizi
69
On 18 Oct 1996 at 11:53:46
I'm delighted to be able to read the initial text of the ODD Aminoglycoside consensus
document. This is exactly the type of thing we need. I would also like very much to review the documents on Vancomycin and Beta-Lactams.
Could anyone tell me where they are?
Bob Brennan
[The ODD Aminoglycoside consensus document is the only one I've seen. Is there anyone
else preparing documents on these other topics? I'd be happy to place the works-inprogress on the server for review and comment - db]
70
S EC T I O N 5
ASA and SA Modeling

On 26 Apr 1996 at 15:04:11
We are interested in modeling and simulation of pharmacokinetics: absorption, tissue distribution and release of acetylsalicylic acid and salicylic acid (ASPEGIC).
We would be interested in any information and references to papers discussing the clinical
studies as well as laboratory.
Abdelkader Ainaoui
Universite Jean Monnet, Laboratoire de Chimie des Materiaux, et Chimie Industrielle, 23,
rue Dr. P. Michelon, 42023 ST-ETIENNE CEDEX 2 FRANCE
On 30 Apr 1996 at 11:13:52
This is for the dog: Chen, C. N., Coleman, D. L., Andrade, J. D., Temple, A. R. 1978
Pharmacokinetic model for salicylate in cerebrospinal fluid, blood, organs, and tissues,
Journal of Pharmaceutical Sciences 67:38-45
Susan E. Shoaf, PhD
On 2 May 1996 at 10:33:02
Reference:
Aarons, Hopkins, Rowland, Brossel and Thiercelin, Pharmaceutical Research 1989 vol 6
(no.8) p660 Routes of administration and sex dierences in the pharmacokinetics of
aspirin, administered as its lysine salt.
This is a paper describing a study performed at Medeval Ltd, in Manchester, England, in
conjunction with Synthelabo, Paris, which may be of use.
71
John Davis
Pharmacokineticist, Medeval Ltd
http://www.man.ac.uk/vuman/med.htm
On 2 May 1996 at 10:33:04
Dear Dr. Ainaout,

You can find relevant information in our recent article:
D. Dubovska, V.K.Piotrovskij et al. Pharmacokinetics of acetylsalicylic acid and its metabolites at low doses: A compartmental modeling. Meth Find Exp Clin Pharmacol, 1995, 17(1):
67-77.
There is there a lot of references to earlier publications about ASA, SA and other metabolites kinetics in man.
Vladimir Piotrovskij, Ph.D.
Janssen Research Foundation, Clinical Pharmacokinetics, Turnhoutseweg 30, B-2340
72
S EC T I O N 6
Aspirin bioavailability
On 2 Dec 1996 at 10:24:50
Hello,
I am a first year pharm. D student who is researching a project comparing 81 mg aspirin
doses brand name vs. generic brands (enteric coated). I have heard that there might be
some biavailability problems with the generic enteric coated aspirin products, but I
haven't been able to find any real data on this. Does anyone have any suggestions?
Brad Hein, RPh
On 3 Dec 1996 at 14:17:41
Dear Bradley,
You might try to search the issue of aspirin kinetics under the name of Gerhard Levy,
PharmD, He "wrote the book" on the issue of aspirin kinetics, dosage form eects, absorption, etc.
Jim Axelson
On 3 Dec 1996 at 17:15:01
You may have already thought of this, but have you referred to the OTC handbook (by
APhA)? Since this is a referenced text, it may contain the citation for your question. Good
luck.
Arasb Ateshkadi, Pharm.D.
Assistant Professor, Department of Pharmacy Practice, College of Pharmacy, University of
Utah, 258 Skaggs Hall, Salt Lake City, UT 84112
73
On 4 Dec 1996 at 10:45:00
It's my impression that companies making generics must file data with the FDA to prove
bioequivalence. You might consider calling the companies and having them send you a
copy of the report they filed with FDA.
Steven C. Ebert, Pharm.D., FCCP
Clinical Specialist, Infectious Diseases, Clinical Associate Professor of Pharmacy, Department of Pharmacy, Meriter Hospital, 202 S. Park Street
74
S EC T I O N 7
AUC calculations
On 22 Mar 1996 at 11:32:47
In calculating the AUC for any particular profile. it is normally correct to use a linear
method for the ascending portion of the curve (up to Cmax) and a log method for the descending portion. This is very straight-forward when dealing with nice, smooth "up and
down" profiles. The question is this - what method(s) should be utilised when a profile
rises to Cmax, then starts to fall, but during the descending phase perhaps concentrations
rise again, but not as high as Cmax, then fall again. Should a linear method be used between two data points when the second point is higher than the first, irrespective of
whether it is post-Cmax, or should a log method be used for all points post-Cmax?
Chris Davie
Department of Pharmacokinetics, SmithKline Beecham Pharmaceuticals R&D
On 25 Mar 1996 at 09:44:47
The theoretical basis for using the log AUC method is founded on the assumption that it
is describing an exponential decline. While wobbling in the region of the peak conc there
is no advantage of the log method (but it is probably not much worse). Trapezoidal AUC is
after all only an approximation suitable for generating initial estimates for non-linear regression models so its not really a big deal either way :-)
Nick Holford
Dept Pharmacology & Clinical Pharmacology, University of Auckland, Private Bag 92019,
75
On 25 Mar 1996 at 09:44:50
This is a very interesting question. We have done PK data analysis for Pharmaceutical companies where multiple peaks in plasma conc-time profile were observed. We used linear
method for the ascending (generally convex in nature) as well as descending (generally concave and log-linear)
portion of the curve (the results of the PK data analysis were also submitted to FDA). The
reasoning being that the linear method usually underestimates the AUC in the ascending
phase, which is somewhat balanced by the overestimation of the AUC in the descending
phase. However, the presence of multiple peaks further complicates the calculation of
AUC. So my suggestion is to use linear method for whole profile unless you have very
strong reasons to use log method for descending portion of the profile.
If it is imperative to use log method for descending profile, I think, real answers can not
be easily found without doing simulation studies with some type of sensitivity analysis.
G. Krishna
Medical College of Virginia, Virginia Commonwealth University
On 26 Mar 1996 at 10:56:53
The linear trapezoidal rule has been proven to give biased estimates of AUC both at the
ascending and descending parts of concentration-time curves. However, since the sampling is usually more frequent before the peak as compared to the tail of the curve, the
bias can be neglected at the ascending part, and also near the peak(s). The log-trapezoidal
rule also results in bias at the ascending part of the curve, however, it gives the exact estimate of areas under descending log-linear profiles (noiseless). If the noise is low (less than
10 %), the log-trapezoidal rule is preferable, especially in cases of long half-lives. It becomes even more important when calculating the first moment (AUMC).
Janssen Research Foundation, Clinical Pharmacokinetics, B-2340 Beerse, Belgium
76
On 27 Mar 1996 at 13:41:06
One approach is based on the sign of the second derivative as described by Proost ( J
Pharm Sci 74: 793-794, 1985) which we have implemented into a "deconvolution " program
(Pharm Res 5: 247-248, 1988).
Gary A. Thompson, Ph.D.
Clinical Pharmacology, Procter and Gamble, 11450 Grooms Rd., Cincinnati, OH 45242
On 28 Mar 1996 at 15:59:29
Concerning the discussion about estimating AUC for noisy or multiple concentration
peak data, people should remember that interpolation and then integration by Lagrange
polynomials is an entirely general method of integration and is independent of the local
concavity or convexity of the data. The Lagrange method was implemented several years
ago by ML Rocci, Jr and WJ Jusko, "LAGRAN program for area and moments in
pharmacokinetic analysis" Computer Programs in Biomedicine 16: 203-216 (1983). One problem with Lagrange method is that it occasionally suers from oscillations yielding poor estimates of area. The Lagrange method and the issue of oscillations is discussed in KC Yeh
and KC Kwan, "A Comparison of Numerical Integrating Algorithms by Trapezoidal, Lagrange, and Spline Approximation" Journal of Pharmacokinetics and Biopharmaceutics (JPB) 6:
79-98 (1978).
R. Purves has done a rigorous comparison of many methods of estimating AUC and
AUMC. I recommend his paper: "Optimum Numerical Integration Methods for Estimation of Area-Under-the-Curve (AUC) and Area-Under-the-Moment-Curve (AUMC)" in
JPB 20: 211-226 (1992). In the paper, Purves describes what he found to be the optimal algorithm for estimating AUC and AUMC. This method involves a parabola through the origin for regions of the concentration curve having negative curvature and the standard log
trapezoidal method elsewhere.
Finally, in the forthcoming April issue of J Pharm Sci is an article by JM Gallo and myself
describing our program NCOMP which implements both the Lagrange method and the
Purves method for noncompartmental analysis of pharmacokinetic data.
Paul B. Laub
77
Dept. of Medical Oncology, 364 West Bldg., Fox Chase Cancer Center, 7701 Burholme
Ave.
Phila. PA 19111 USA
78
S EC T I O N 8
Bayesian pharmacokinetics
On 21 Jun 1996 at 14:44:24
Can anyone suggest some references which I can read which describe the basic foundational principles underlying bayesian pharmacokinetics? I would especially like a few
sources which just go over the basic principles without getting too technical. I've heard
that Bayes theorem represents some kind of statistical technique using population parameters or something. I've seen it compared in studies and advertised in pharmacokinetic programs to "traditional" pharmacokinetic techniques but have never had a really good conception of what is represents or how to utilize it. Any help would be greatly appreciated.
Thanks
Randy Kuiper, RPh.
Great Falls, MT
On 21 Jun 1996 at 22:51:48
There are several articles written on Bayesian theory relating to pharmacokinetics.

Sheiner LB, Rosenberg B, Melmon KL. Modelling of individual pharmacokinetics for
computer-aided drug dosage. Computers and biomedical research 1972; 5: 441-459. (One of
the original articles)
Sheiner LB, Beal SL, Rosenberg B, et al. Forecasting individual pharmacokinetics. Clinical
Pharmacology and Therapeutics 1979; 26: 294-305.
Sheiner LB, Rosenberg B, Marathe VV. Estimation of population characteristics of pharmacokinetics parameters from routine clinical data. Journal of Pharmacokinetics and Biopharmaceutics 1977; 5: 445-79.
79
Sheiner LB, Beal SL. Bayesian individualization of pharmacokinetics: Simple implementation and comparison with non-bayesian methods. Journal of Pharmaceutical Sciences 1982;
71: 1344-8.
Schumacher GE, Barr JT. Bayesian approaches to pharmacokinetic decision making.
Clinical Pharmacy 1984; 3: 525-30. A straightforward simple review.
Vozeh S, Steimer JL. Feedback control methods for drug dosage optimisation. Concepts,
classification and clinical application. Clinical Pharmacokinetics 1985; 10: 457-476.
I hope these references help.
Michael Burton
On 24 Jun 1996 at 10:39:29
As the matter of fact, there is no Bayesian pharmacokinetics. There is a method of obtaining individual estimates of PK parameters from few measurements (not sucient to get
them in a standard way by fitting a model to these measurements) which is called Bayesian
individualization. To apply it, you should know (i) the PK model, (ii) population averages
of model parameters, (iii) inter-individual variability in these parameters, and (iv) residual
(intra-individual) variability in your measurements not explained by inter-individual dierences in PK parameters. Then, you need a nonlinear regression program which minimizes
an objective function of special form called Bayesian objective function.
In addition to the references given by Michael Burton I would recommend several more
recent publications:
Proost, J.H. Adaptive control of drug dosage regimens using maximum a posteriori probability Bayesian fitting. Int J Clin Pharm Therapeutics, 1995, 33: 531-536.
Wakefield, J. and Racine-Poon, A. An application of Bayesian population pharmacokinetic/
pharmacodynamic models to dose recommendation. Stat Med. 1995; 14(9-10):971-986.
Tanigawara, Y.; Yano, I.; Kawakatsu, K.; Nishimura, K.; Yasuhara, M., and Hori, R. Predictive performance of the Bayesian analysis - eects of blood sampling time, population parameters, and pharmacostatistical model. Journal of Pharmacokinetics and Biopharmaceutics.
1994; 22(1):59-71.
80
El-Desoky, E.; Meinshausen, J.; Buhl, K.; Engel, G.; Haringskaim, A.; Drewelow, B., and
Klotz, U. Generation of pharmacokinetic data during routine therapeutic drug monitoring: Bayesian approach vs pharmacokinetic studies. Ther. Drug. Monit. 1993; 15(4):281-288.
You can find a lot of references to more specific publications in these papers.
On 25 Jun 1996 at 12:10:48

Perhaps a statement on Bayesian methodology of pharmacokinetic analysis and its costutility in a clinical setting would be a useful topic, vis a vis our previous discussions on consensus statements.
Steven Ebert
81
S EC T I O N 9
Body surface area calculation

On 18 Oct 1996 at 13:57:23
I need to convert a human drug dose in mg/(meter squared) to a comparable dose in rats.
How does one calculate the surface area of a rat. Is there a formula? In addition, how can
the human dose be converted into a rat dose on a mg/kg basis?
Tom Wallace
On 21 Oct 1996 at 09:50:31

I do not know how to calculate the surface area of a rat! .... but I think you don't need to. I
have always used the conversion 1 mg/kg = 6 mg/sq.m for rats. (In mice 1 mg/kg = 3
mg/sq.m). Therefore you should be able to work out an appropriate dose if you know the
mg/sq.m dose in man.
Hope this is helpful - others may disagree, it will be interesting to see if there any other
comments.
Duncan Jodrell
Edinburgh
On 21 Oct 1996 at 09:50:45
It depends upon the rat and the person. The questions you ask are spelled out in:
Freireich EJ et al. Quantitative comparison of toxicity of anticancer agents in mouse, rat,
hamster, dog, monkey and man. Cancer Chemo Reports 1966; 50:219-244.
Another paper to look for is:
82
Monro A, and Mordenti J. Expression of exposure in negative carcinogenticity studies:

dose/body weight, dose/body surface are or plasma concentrations? Toxicolgy Pathology
1995;23:187-98.
which has a comprehensive table describing physiological dierences between rats and humans to guide your allometric conversions.
Joan Korth-Bradley
On 21 Oct 1996 at 09:51:25
A good reference to start with is 'First-time-in-human dose selection: Allometric thoughts

and perspectives, by Boxenbaum and Dilea, J.Clin.Pharmacol. 35:957-966(1995).
Johan Gabrielsson
On 22 Oct 1996 at 11:08:50
You could use pharmacokinetic-based approach to convert human dose to rat dose using
AUC or PBPK methods. These are outlined in a review written by Voisin et al., entitled
"Extrapolation of animal toxicity to humans: interspecies comparisons in drug development" that appeared in Regulatory Toxicology and Pharmacology. 12(2): 107-116, 1990 (October).
Rajesh Krishna
83
On 22 Oct 1996 at 11:10:01
Species
Mouse
Rat
Monkey
Dog
Human
Child
Adult
Body Wt. Body Surf.

Km Factor
(Kg)
Area (m2)
0.2
0.15
3.0
8.0
0.0066
0.025
0.24
0.40
3.0
5.9
12
20
20.0
60.0
0.80
1.60
25
37
Ref: Freireich E.J. et.al. Cancer Chemother. Reports 1966, 50(4) 219-244.
Body Surface area dependent Dose conversion
Rat (150g) to Man (60 Kg) is 1/7 the rat dose
Dog (8Kg) to Human (60 Kg) is 1/2 the dog dose.
Prasad Tata, Ph.D.
Otsuka America Pharmaceuticals Inc.
On 13 Nov 1996 at 11:37:07
Calculation of APPROXIMATE body surface area (BSA) uses simple allometric relationship based on body weight (W):
BSA = W to the 0.67 power.
The Freireich data are reanalyzed (by allometric approach) in "Dosage Regimen Design
for Pharmaceutical Studies Conducted in Animals," J. Mordenti, J. Pharm. Sci., 75:852-57,
1986. A good discussion on allometry and tables of BSA data appear in "Extrapolation of
Toxicological and Pharmacological Data from Animals to Humans," W. Chappell & J. Mordenti, Advances in Drug Research, Vol. 20, 1-116, 1991 (published by Academic Press Ltd).
Joyce Mordenti
84
PS Joan, I was surprised by your plug for the Monro/Mordenti paper. I didn't expect
many pharmacokineticists to discover it. Thanks!
On 14 Nov 1996 at 12:11:21

Calculation of APPROXIMATE body surface area (BSA) uses simple allometric relationship
based on body weight (W):
BSA = W to the 0.67 power.
But why use BSA in preference to more empirically sound allometric models?
The only thing going for BSA is tradition. The usual Du Bois & Du Bois model for BSA is
based on 10 individuals. An allometric exponent of 3/4 instead of 2/3 is based on a multitude of observations across several orders of magnitude of weight and varieties of animals.
See:
Peters RH. The ecological implications of body size. Cambridge: Cambridge University Press, 1983
This is THE reference work for a wider view of allometrics.
Holford NHG A Size Standard for Pharmacokinetics Clin. Pharmacokin. 1996;30:329-332
Compares common size models for clearance and shows the potential weakness especially
at low body weights e.g. children in comparison to the 3/4 exponent model.
Nick Holford
85
S EC T I O N 10
Body weight
On 16 Feb 1996 at 10:01:58
Does anyone know if we can use the formula: ClCr = (140- age)*weight/70 or 85 for female
to estimate body weight of a patient ?
Because I know the daily creatinine clerance and I know the age. So it could may be possible to estimate body weight. But this formula has may be some restrictions ? (severity of
the renal function) My patients are staying in intensive care unit and it's not possible to
weigh these patients.
The estimation by sta was not practicable.
Nicolas Van Brandt
Pharmacist, Lab. of Pharmacokinetics (Prof R.K. Verbeeck), University of Louvain, Av E.
Mounier, 73-55, 1200 Brussels, Belgium
On 16 Feb 1996 at 10:01:59
CLCr = [(140-age)*(body mass)]/[SrCr*72]

Multiply by 0.85 for females. This nomogram has a high correlation among the variables,
so solving for body mass would give a good estimate. One would still have to consider the
body *type*, ie, is the patient obese (larger proportion of fat) or particularly lean (larger
proportion of muscle).
After estimating the mass, it would be a good idea to calculate lean body mass, which
would require knowing the height (or length, in this case) of the patient, because on e of
the factors determining the rate of creatinine production is muscle mass--of two people
weighing the same, the one with a larger proportion of skeletal muscle would produce
more creatinine.
Randy Trinkle
86
Dept. of Pharmacy, Dawson Creek & District Hospital, Dawson Creek, BC, Canada
On 19 Feb 1996 at 10:23:13
It is certainly possible to obtain an ESTIMATE of weight (actually, something closer to

ideal weight). Remember, however, that the coecient of determination (R2) for this relationship is not more than about 0.7 and there will be fairly large error in the estimate. To
the best of my knowledge your question has not been answered experimentally. Good
luck!!
Michael Mayersohn
College of Pharmacy, University of Arizona, Tucson, Arizona 85721
On 19 Feb 1996 at 10:23:16
I would think that formula relates to a normal population with normal renal function. I
would be very cautious about using it to estimate the weight of patients in intensive care,
many of whom have grossly impaired renal function. If you think about anuria as being
one extreme (a regular situation in intensive care) the answer to the formula is a nonsense
and a patient who was almost anuric would weigh almost nothing. I think you should look
at some alternative ways to estimate weight.
Ken Newton.
On 19 Feb 1996 at 10:23:18
I am a Pharm D. student from Idaho State University. Recently I completed a class on

clinical research and design. This class included lots of statistics and mathematical models. One thing the professor pounded into our heads is that when doing a linear regression, such as estimating CrCl from weight and serum creatine, or estimating kel for aminoglycosides from CrCl, YOU CANNOT GO BACKWARDS. Estimating CrCl from predictor variables like weight and serum creatinine is good, but what area good predictor
variables for weight? Is the patient hypermetabolic, receiving adequate nutrition, third
spacing, recieving adequate hydration. There area a lot of variables that go into why a patients weight may fluctuate, not just CrCl.
87
I work at a 250 bed tertiary care facility with about 35 ICU beds. I am not sure what your
facilities' resources are, but our beds are capable of weighing the contents of the bed. thus
the patient. Each day the nurse pushes a button and the bed tells him/her the patients
weight. I am sure there is more to it than that, but it is a very good way to monitor a patients weight.
SD Beyer
On 19 Feb 1996 at 10:23:22
I guess the estimations by sta would be not less accurate than those obtained via the formula.
Vladimir Piotrovskij
On 19 Feb 1996 at 10:23:24
I would be hesitant to use such an estimator to go back to establishing weight. It might

be acceptable to establish a guess to correlate with guesses of the sta. The degree of variability might be as high as you could get from having two or three sta make an educated
guess. Good luck.
John E. Murphy, Pharm.D.
Professor and Head, Department of Pharmacy Practice and Science
On 20 Feb 1996 at 10:46:51
A useful starting point to estimate the weight of non-ambulant patients may be the following paper
Atiea JA, Haboubi NY, Hudson PR, Sastry BD. 1994 Body weight estimation of elderly patients by nomogram. Journal of the American Geriatrics Society, 42, 763-765.
Roger Rumble, PhD
Tasmanian School of Pharmacy, University of Tasmania, GPO Box 252C, Hobart, Tasmania, 7001 AUSTRALIA
88
S EC T I O N 11
Chiou Method
On 19 Nov 1996 at 17:08:49
I do grading for a pharmacokinetics course. One of our students has asked me about the
Chiou (not sure of the spelling here) relationship used for determining clearance of dig
and procainamide. They'd like to know if there's a paper or book out there that discusses
proper usage of this equation. I've looked through all my resources and come up empty.
Any input from you folks would be greatly appreciated.
Catherine Heyneman, Pharm.D., ISU College of Pharmacy, Pocatello, ID 83209
On 20 Nov 1996 at 15:59:29
I think the reference you are seeking is: Chiou, W. L., Gadalla, M. A., and Peng, G. W.
(1978). Method for the rapid estimation of the total body drug clearance and adjustment of
dosage regimens in patients during a constant-rate intravenous infusion. Journal of Pharmacokinetics and Biopharmaceutics, 6(2), 135151.
Varun Garg
Otsuka America Pharmaceutical, Inc.
On 25 Nov 1996 at 10:09:09
The reference for the Chiou paper is:

Chiou, W. L., Gadalla, M. A., & Peng, G. W. (1978). Method for the rapid estimation of the
total body drug clearance and adjustment of dosage regimens in patients during a
constant-rate intravenous infusion. Journal of Pharmacokinetics and Biopharmaceutics, 6(2),
135151.
This method can be used for any drug that is given by continuous infusion. All that is
needed to derive a clearance value is the rate of infusion, a population volume of distribu89
tion (L/kg*whichever weight is appropriate for the drug (IBW, DW, TBW)), and two serum concentrations drawn after the beginning of the continuous infusion preferably 1-2
half-lives apart, and the time dierence between those concentrations.
The equation is:
CL =
2Vd * (C1 C2)

2Ro
+
C1 + C2 (C1 + C2) * (t2 t1)
Where Ro = infusion rate in mg/h

Vd = population Volume of distribution in L
C1 = first serum concentration drawn after beginning infusion
C2 = second serum concentration drawn after beginning infusion
t1 = time of C1
t2 = time of C2
Although this equation is commonly used with theophylline, it can be used with intravenous procainamide. I don't believe it has an application with digoxin since it is administered either orally or IV push.
Michael Burton
90
S EC T I O N 12
Consensus documents
On 12 Jun 1996 at 11:16:09
Most of the messages and discussions going on in the list are interesting, although somewhat unconnected. Probably, this is the intention of a list on
the Internet. However, to show ourselves and others ('our skeptical colleagues') that the
lists on the Internet are a useful and ecient tool for the progress of health care sciences,
I suggest that we prepare 'Consensus Statements' on topics related to our list. We all have
sound scientific knowledge and/or clinical experience in the field of pharmacokinetics to
be able to prepare valuable documents for the benefit of our colleagues and the care of our
patients.
Possible schedule:
1.
A member of the list suggests a topic and a co-ordinator (himself?).
2. The co-ordinator prepares a basic document.

3.
The basic document is sent through the list to all members (as an attachment).
4. For a given term (2 weeks?), those who wish to participate and contribute to the Consensus Statement should sent their comments and amendments to the co-ordinator.
5.
The co-ordinator produces a second document.
6. The second document is e-mailed to those who have significantly contributed to it for
final consideration.
7. For a short term (1 week?), last comments and amendments may be sent to the coordinator.
8. The co-ordinator prepares a final document and sends it for publication to an adequate journal.
91
An example: Consensus statement on once-daily dosing of aminoglycoside antibiotics by

the Internet PharmPK list contributors: A, B, C, ... X
Will we not be able to do it?.
Cris Ronchera-Oms
Hospital Pharmacist, Valencia, Spain
On 13 Jun 1996 at 11:17:07

However, to show ourselves and others ('our skeptical colleagues') that the
lists on the Internet are a useful and efficient tool for the progress of
health care sciences,
I don't think this should be the primary reason i.e. to convince the sceptics. A better reason would be because we wish to advance our science by collaborating to produce a review
document. I certainly support the concept. It does not have to be a consensus view. If
there is controversy then this should be reviewed as well. I would also like to suggest that
consideration is given to creating an HTML version of the document at an early stage.
8. The co-ordinator prepares a final document and sends it for
publication to an adequate journal.
As Consulting Editor for 'Clinical Pharmacokinetics' I would be delighted to consider

such a document for publication.
Nick Holford
On 13 Jun 1996 at 11:17:08
Cristanto!
Your idea concerning consensus documents is very good. I will no doubt add some element of organization to the group. It will, however, require some fine tuning before a "con-
92
sensus" is reached on the final format. I have a topic or two that I would be very interested in getting everybody's opinion about.
However, this new "activity" should not replace the current free-flow format because it
has its advantages despite the apparent incoherence at times. I find your suggestion worthy of support and discussion.
N. Anaizi, PhD RPh
Univ. of Rochester Medical Center
On 13 Jun 1996 at 11:17:09
With all due respect, I VOTE NO to this suggestion. It is too structured and artificial and
academic. It will result in a weekly pontificator and/or a myopic dialogia.
On 13 Jun 1996 at 15:45:24
Dear Chris,
Sounds like a good idea. The only problem I have is that I have to make time at the end
of my day to read the mail I currently receive (5 lists). I would be interested in reading the
kinetics material but am not sure how much time I could devote to contributing to the discussion, if indeed my contribution would be of merit. In any case, if there a sucient
number of pharmacist out there willing to help out, you can count me in. We will depend
on your leadership or possibly the leadership of our fearless coordinator of this list for this
project.
Robert Aucoin RPh
Peds Clincial Pharmacist, BRLA OLOLRMC
93
On 19 Jun 1996 at 13:33:42
Dear Colleagues,
I have received significant feed-back on the initial proposal to prepare consensus/review
documents through the PharmPK list. Although one clearly negative opinion has been expressed, the proposal has received a warm acceptance (9 messages). Furthermore, Dr.
David Bourne (co-ordinator of the PharmPK list) has also expressed a positive view. After
gathering all the information, it seems possible to conduct this new activity through our
list. It should not interfere much with the normal free-flow in the list, since only the initial/ intermediate/final documents will be circulated to all members, but not the amendments and comments, which must be e-mailed directly to the co-ordinator designated for
each individual document. Consequently, much of the trac will be o the list, and the
group will be kept up-to-date and able to contribute.
Main objective: To prepare consensus/review documents on selected pharmacokinetic topics for the advance of scientific knowledge and health care. (Please note that these documents have not a predetermined format nor length).
Secondary objectives:
1.
to activate and to promote the PharmPK list.
2. to show that lists on the Internet are a valuable and ecient tool for the advance of
health care sciences.
Participants: members of the PharmPK list.
Sources: bibliographic material, own research and/or clinical experience.
Possible schedule (although it will probably be more flexible):
1.
A member of the list identifies a topic worthy of review and/or consensus, suggests the
topic and a co-ordinator.
2. The co-ordinator prepares a basic document.

3.
The basic document is posted through the list to all members.
4. For a given term, those willing to participate and contribute to document should post
their comments and amendments directly (e-mail) to the co-ordinator.
94
5.
The co-ordinator produces a new document.
6. These new document/s is/are again circulated through the list for re-consideration.
7. Finally and for a short term, last amendments and comments may be posted (e-mail) to
the co-ordinator.
8. The co-ordinator prepares a final document and sends it for publication to an adequate journal. An WWW version will also be produced.
CALL FOR PROPOSALS: * topic (title): * co-ordinator (name and e-mail address): * term
to have the basic document ready (date):
Cris Ronchera-Oms, Valencia, Spain.
On 27 Jun 1996 at 11:33:26
Dear Colleagues,
Four dierent issues have already been identified and proposed on which useful consensus/
review documents could be prepared. These are:
1.
Utility of monitoring vancomycin serum concentrations.
2. Continuous infusion of beta-lactam antibiotics.

3.
Once-daily dosing of aminoglycoside antibiotics.
4. Cost-utility of bayesian methodology of pharmacokinetic analysis in the clinical setting.

This message is a call for individuals willing to act as co-ordinators for any of these topics
(or others that they may propose).
95
On 9 Jul 1996 at 09:29:31
Dear Colleagues,
These are the topics on which consensus documents will be prepared and the coordinators
appointed for each topic:
1.
Utility of monitoring vancomycin serum concentrations, Dr. Douglas C. Anderson, Department of Clinical Pharmacy Practice, University of Mississipi School of Pharmacy
2. Continuous infusion of beta-lactam antibiotics, Dr. Les White and Dr. Alasdair
MacGowan, Department of Microbiology, Southmead Health Services NHS Trust,
Bristol, UK
3.
Once-daily dosing of aminoglycoside antibiotics, Dr. N. Anaizi, University of Rochester Medical Center
We would like to encourage you to e-mail any information (text, comments, references)
that you may consider of value directly to the coordinator (not through the list).
For each topic, the coordinator will prepare a basic document to be posted to and reviewed by all members of the PharmPK list.
On 9 Jul 1996 at 09:29:35
Dear Colleague,
We have recently introduce a new discussion format aimed at integrating the varied opinions of the participants concerning a given topic into a "consensus document", which may
be published for the benefit of professionals, educators, and students.
The first topic has been chosen; it is the "once-daily dosing" of aminoglycosides, and I
have been asked to be the coordinator of the discussion. To launch the discussion, the coordinator first prepares and posts a initial document to be thoroughly dissected and discussed by you to help the coordinator prepare the final consensus document for publication.
96
However, before I prepare the initial document, I would like us to better define our primary objectives, i.e., the main issues that should be emphasized. The reason is simple - we
would like to bring the relevant issues into focus and contribute new and useful insights; I
do not think that we should aim to write another review article. During the last five years,
over a hundred articles addressed directly or indirectly this topic. These included reports
on original randomized clinical trials, in vitro studies, animal studies, accounts of clinical
experience, meta-analyses, review articles, book chapters, and newsletters. Here are a few
good reviews:
1- Barclay ML, Begg EJ, Hinckling KG. 1994 What is the evidence for once daily aminoglycoside therapy? Clin Pharamcokinet 27, 32-48
2- Gilbert DN. Aminoglycosides. In Mandel GL, Bennett JE, Dolin R. Principles and
Practice of Infectious Diseases. 4th ed. 1995 Churchill Livingston, NY.
3- Preston SL, Briceland LL. 1995 Single Daily Dosing of Aminoglycosides. Pharmacotherapy, 15 297-316.
The "once-daily" or "single-daily" or "pulse" dosing of aminoglycosides was first used by Labovitz in 1974 and rediscovered in the late 1980s. It gained popularity worldwide year after
year. A survey conducted in the USA in 1994 by Schumock and co-workers (Pharmacotherapy 1995, 15 201-209) estimated that in the USA over 25% of hospitals of 400 beds or
larger used the qd dosing routinely. Currently many centers are adopting to the "once-daily
aminoglycosides" as their standard practice. However, we have no solid, updated information concerning:
1. the relative number of institutions/ hospitals that have adopted this dosing method as
their standard (preferred) method. In the USA, the adoption process usually involves the
"Pharmacy and Therapeutics" committee. 2. the "ocial" guidelines for its use (dose, conditions excluded, monitoring criteria, etc.).
I believe that we should first make a good eort to gather this type of information. Our
group (PharmPK) and our medium (the InterNet) are best suited for this task. So please
check the hospitals in your town and forward the above information to me along with a
very brief description of each hospital (size, type of care, etc).
97
In addition, please let me know what you think should be the main focus of our consensus
document.
N. Anaizi
University of Rochester Medical Center
On 10 Jul 1996 at 11:17:22
The important questions which need to be answered are:

CAN once-daily dosing of aminoglycosides be done successfully?
SHOULD once-daily dosing of aminoglycosides be done?
How often will deviation from the methods (i.e., patients selected, duration of therapy,
etc.) described in the primary literature be necessary when this method is adopted in a
given institution?
What role doses serum concentration monitoring play? What, if any, serum concentrations should be obtained? What are "therapeutic" concentrations?
In patients with reduced CrCl, should the daily dose be reduced, or the interval lengthened?
Should patients with infections of dierent severity ("mild", "moderate", "severe") receive
dierent maximal daily doses?
Steve Ebert
On 11 Jul 1996 at 09:36:11

The important questions which need to be answered are:
CAN once-daily dosing of aminoglycosides be done successfully?
SHOULD once-daily dosing of aminoglycosides be done?
Some observations, perhaps an answer in the bunch... Once daily aminoglycoside dosing
is currently being done successfully at several institutions in our state. The starting dose is
5mg/kg q24h. A trough is drawn 2 to 3 hours before the next dose. This gives time to the
98
attending MD or clinical pharmacist to access the timing of the next dose. Peaks are
drawn 12 to 14 hours after the dose (mid-point).
Dierent bugs require dierent peaks to do the job. The literature is plentiful of high
peaks (10-12) getting maximum penetration and the low troughs (0-.2) giving the bugs a
false sense of security and dropping their guard. Thats the easiest way to put it.
We don't do this in pediatrics. Docs won't hear of it and I agree. I have a hard time convincing them to give 2.5mg/kg as a loading dose. Also with kids who have a CrCl of
>130ml/min we would have to give 7 to 9 mg/kg for the eect to even last 24 hours. A second hard sell. Not one I'm willing to engage in.
There is plenty of literature out there. Most of it was reviewed here and on the PharmPK
list and a couple on the Hospital US list in the past six months.
ODAD is an idea that will either sell in your hospital now or sell later. Either way we still
have to monitor to stop them from cooking kidneys.
Robert Aucoin RPh
Peds Clinical Pharmacist, OLOLRMC Baton Rouge, LA
99
S EC T I O N 13
Creatinine Clearance Calculation - Age

On 6 Feb 1996 at 12:55:47
I am trying to determine the eects of age and renal function on the clearance of a drug.
The Jellife and Cockcroft and Gault methods to determine creatinine clearance from serum creatinine concentrations include the patients age in the calculations. The inclusion
of age in the creatinine clearance calculation may be confounding the determination of
the eects of age and renal function on drug clearance. Are there any other accurate methods for calculating creatinine clearance from serum creatinine concentrations that do not
include subject age in the equations?
Ben Suttle
Zeneca Pharmaceuticals
On 7 Feb 1996 at 10:04:10
Because of the age related decline in renal function, I think that it will be dicult to separate the determination of renal function from a serum creatinine value in a predictive algorithm without considering age. I would suggest that 8 or 24 hour urine collections be performed in an experimental situation to separate the eects of age from renal function. Although the current gold standard is probably non-radioactive iothalamate clearance using
a continuous infusion with three timed urine collections and mid-point serum concentrations over 3 hours.
Michael Burton
On 8 Feb 1996 at 12:26:09
Creatinine clearance estimates are based on the input/output principle. The role of age,
weight, etc. in the equations are simply estimates of the rate of endogenous production of
100
creatinine which is the rate in (input). The rate out (output) is the creatinine clearance,
and the ratio of the two is equal to the serum creatinine.
Creatinine porduction is know to decrease with age. If you leave it out of the estimation
formula, you are neglecting a known variable. Why not measure drug clearance or elimination directly? I have published a couple of papers in which we measured drug clearance directly using limited sampling.
Art Harralson, Pharm.D., BCPS
Professor and Vice-Chairman, University of the Pacific, School of Pharmacy
On 8 Feb 1996 at 12:26:10
To Ben Suttle, Zeneca Pharmaceuticals:

I assume your drug of interest is >50% renally cleared, otherwise what follows is not very
relevant. I don't think you can get around this problem easily since age is one of the major
determinants of declining CrCL after the age of 25 or so. Furthermore (as you probably
know) serum Cr levels can be notoriously misleading in estimating CrCL in elderly patients, in nutritional deficiency or metabolic disorders when decreased Cr production by
muscle tissue can mask diminishing renal function. Therefore, why not be done with it
and do a 24 hr urine collection, a 12 hr serum level and assay both for creatinine to directly
estimate the "true" CrCL? Alternatively, some other direct way to estimate GFR would be
OK, e.g. as suggested in the reply from Michael Burton.
Bruce Charles, PhD
Pharmacy Dept, Univ. Queensland, Brisbane, Australia
101
S EC T I O N 14
Creatinine Clearance Calculation - Weight,

Age, Serum Creatinine
On 5 Dec 1996 at 10:32:43
I have a few questions about calculating CrCl that I hope someone can help me with. Currently my hospital has started a policy of monitoring CrCl by pharmacy, a good idea, but
the problem is we cannot all agree on the 'correct' formula to use. Most of us use ideal
body weight in the formula [(140-age)*IBW]/72* SCr (*0.85 for female).
1. Some have used dosing weight in place of IBW in pt's greater than 20% above IBW. Is
this justified?
2. Some have suggested normalizing for BSA. Has this been shown to be more/less accurate?
3. Some have rounded SCr up to 1 for pt's older than 65. Is this appropiate?
We would like to standardize on one way of calculating CrCl so as not have conflicting recommendations, as have already happened. Thanks in advance for any information.
Chris Humble
Albert Einstein Med Ctr
On 6 Dec 1996 at 10:31:06
IBW. Is this justified?

Not really ! The so-called dosing weight is good for dosing aminoglycosides and similarly
distributed drugs. In the case of creatinine clearance, you need Lean or Ideal Bdy Mass
(LBM or IBM) because it provides a more "accurate" parameter of muscle mass, and
hence of the rate of creatinine production. However, for practical purposes whether you
use LBM or DW what you get is still a ROUGH estimate of GFR, and hence of renal func102
tion. This "ROUGH ESTIMATE" is however still very useful for the purpose of dose adjustments.
2. Some have suggested normalizing for BSA. Has this been shown to be >more/less accurate?
Normalizing for BSA is great for comparison purposes, and for drawing general guidelines
and nomograms. Drug elimination is eected by the actual (non-normalized) glomerular
filtration rrate and/or tubular secretion rate. For your purposes (and ours) normalizing is
unecessary.
3. Some have rounded SCr up to 1 for pt's older than 65. Is this appropriate?
I have seen arguments for it and against it. I happen to use this shortcut routinely for elderly female pts to get a "quick & dirty" estimate as opposed to a rough estimate of CLcr.
The more important issue is how to estimate CLcr in elderly pts with low muscle mass
(e.g., muscle atrophy or emaciated pts). In this case rounding to one is not enough. Estimating creatinine clearance in these pts has always been problematic. In these patients the
serum creatinine is often deceptively low or "normal", and the Cockroft equation (Nephron '76; 16: 31-41) yields inaccurate estimates of renal function. However, recently
SANAKA and his co-workers (Nephron 1996; 73: 137-144) developed an equation that gives
CLcr values that are close to those obtained by direct measurement of creatinine clearance using 24-hr urine collections.
For males: CLcr = BW (19 Alb + 32) / 100 Scr For females: CLcr = BW (13 Alb + 29) / 100
Scr
Where: BW = actual body weight in kgs; Alb = serum albumin in grams / dL; and Scr = serum creatinine in mg/dL.
In conclusion, while it is good to try to obtain as accurate an estimate of CLcr as possible,
the important issue is what to do with it once you get it. Let this be our thread for future
discussions on this topic....
N. Anaizi, PhD RPh
Univ. of Rochester Med Center
On 6 Dec 1996 at 10:33:16
103
The Cockroft & Gault formula quoted for estimating CrCl can and does require actual
body weight. Ideal body weight may be OK in normal circumstances but in overweight persons this may be misleading. there is no harm in normalizing to BSA (1.73 sq m). I know
that in diabetics the CrCl using this formula (using actual weight) has been tested by comparing it with radio-isotopic method with very good agreement (Sampson & Drury, 1992,
Diabetes vol 15 p609-). In my experience this formula also gives correct estimates of CrCl
in HIV subjects when using actual weight when compared to actual renal clearances of creatinine. You may find that renal clearance of creatinine overestimates true GFR by some
15-20% in healthy subjects and in HIV (Noormohamed et al. Br J Clin Pharmacol, (1997)
vol 47 (in press). My limited experience with patients with a single kidney also shows that
the formula can be used confidently and compares well with true GFR measured using
51Chrome-EDTA.
By the way the formula works just as well when using serum creatinine expressed in
micromol/l. In such cases the formula is (140-age[y]) X body weight [kg] X K/serum
creatinine[micromol/l) where K = 1.23 for male and 1.05 for female subjects.. Hope this is
useful.
Faruq H Noormohamed
Department of Therapeutics, Chelsea andWestminster Hospital, 369 Fulham Road LONDON SW10 9NH
On 6 Dec 1996 at 10:33:33
There is a good discussion of creatinine clearance formulae in DiPiro's Pharmacotherapy.

The discussion states that the Cockroft-Gault equation was originally done with ABW not
IBW or DBW.
See also Murphy JE, ed. Clinical Pharmacokinetics (pocket reference). ASHP, 1993, pages
xxxv-xxxvii. These latter two references caution on STABLE vs CHANGING renal function, as well.
Also: Davis GA, Chandler MH. Comparison of creatinine clearance estimation methods
in patients with trauma. American journal of health-system pharmacy 1996 May 1;
53(9):1028-32. This article helps point out some issues with adjustments, etc., also.
104
We have a similar problem here. Our decision (for purposes of a standardized and consistent way to REPORT an estimate of the patient's CrCl) was to use the Jelie formula
(114-0.8(Age)/SCr, females 85% of this). This is reported out in our institutions lab results
(it is automatically calculated every time a SCr is done on a patient). It bypasses the need
for weight (retrieving a height and weight on a patient is not always possible or done!), and
has a disclaimer stating that the estimate is about 9% greater than actual.
Our Pharmacy order-entry computer (Cerner) automatically calculates using C-G (based
on IBW) when we enter height and weight. The bottom line is for a screening process:
which patients have bad renal function.
My personal approach is to look at the screening data (or just the patients age) and determine where to go next. I try and look at many factors, most specifically age, nutritional
status (+ or -), and concurrent disease states. I try to find the factors about the patient that
will aect how I look at their SCr, usually those that I feel who's SCr will NOT reflect
their true renal function (i.e., malnourished patients, patients with liver disease, etc.) This
latter aspect addresses the "rounding up" issue you mentioned. I do not do it, and I believe my colleagues do not either. (There was a recent article that addresses this within the
past few years that escapes me at this writing, sorry!) I personally use C-G wehen I know
the RF is stable, and then judge where I feel the patient will trend toward during my monitoring processes.
Bottom line: use whatever formula to screen and/or initial CrCl estimate, then use your
clinical judgement and experience and talking with colleagues when faced with dicult
(presumed or real) patients.
Marc Semprebon, RPh, MSLS
Dartmouth-Hitchcock Medical Center, Lebanon, NH
105
On 6 Dec 1996 at 10:36:00
I mis-represented information in my previous note regarding the Jelie formula and our
reporting of CrCl. Our comments about the estimated clearance is "As agroup, this estimate appears to be about 9 ml/min (not %) less than actual measured clearance. However,
in an individual patient, the estimate is within +/- 20 ml/min 2/3rds of the time, when compared to actual measured value."
Dartmouth-Hitchcock Medical Center, Lebanon, NH
On 9 Dec 1996 at 16:30:20

IBW. Is this justified?
If you consider the fact that creatinine is produced in the muscle tissues, rather than adipose tissues, then the use of anything but IBW is not justified.
2. Some have suggested normalizing for BSA. Has this been shown to be more/less accurate?
In general, CrCl is not an accurate nor precise measure of renal function, but it is the easiest method we have available in clinical practice. Nonetheless, normalizing CrCl values for
a BSA of 1.73 m2 (roughly 70 kg) allows a fair comparison between individuals of dierent
body habitus. I am assuming that pharmacy is in charge of calculating CrCl primarily for
the purpose of dosing renally excreted/metabolized drugs. In that regard, one has to be
careful in basing the dosing regimen on normalized CrCl, since the original PK study for a
specific drug may not have normalized subject's CrCl (many do, however).
3. Some have rounded SCr up to 1 for pt's older than 65. Is this appropriate?
This does not seem appropriate since I can't figure out why a value of 1 is chosen. I am assuming it is because it is a round number. In such patients, a 24-hour collection is necessary.
Assistant Professor, Department of Pharmacy Practice, College of Pharmacy University of
106
On 10 Dec 1996 at 10:59:18

If you consider the fact that creatinine is produced in the muscle tissues, rather
than adipose tissues, then the use of anything but IBW is not justified.
Your statement about IBW is a bit too strong. The idea is to predict creatinine production
rate and in part this can be done using a measure of body size to predict muscle mass.
IBW is computed from gender and height. Total body weight in a person of "normal" body
composition has been the basis for the standard CPR formulae and for this empirical reason it should be preferred over IBW. In people with abnormal composition especially obesity then IBW may be better than TBW when there is an excess of muscle free mass aka
fat. I am not aware of any reported study that has examined IBW as a predictor of CPR.
Does anyone know of one?
Nick Holford
On 11 Dec 1996 at 12:34:14
If you consider the fact that creatinine is produced in the muscle tissues,
rather than adipose tissues, then the use of anything but IBW is not justified.
Your statement about IBW is a bit too strong. ...... I am not aware of any reported
study that has examined IBW as a predictor of CPR. Does anyone know of one?
Those interested in a study of creatinine clearance estimators and the IBW v. TBW question may be interested in the following paper:
Hallynck T, Soep HH, Thomis J, Boelaert J, Daneels R, Fillastre JP, De Rosa F, Rubinstein
E, Hatala M, Spousta J and Dettli L, Prediction of creatinine clearance from serum creatinine concentration based on lean body mass. Clinical Pharmacology &Therapeutics 30(3):
414-21, 1981.
Joseph Balthasar, PhD
SUNY at Bualo, Pharmaceutics
107
On 12 Dec 1996 at 10:27:23

Your statement about IBW is a bit too strong. ...... I am not aware of any reported study that has examined IBW as a predictor of CPR. Does anyone know of
one?
Those interested in a study of creatinine clearance estimators and the IBW v. TBW question may be interested in the following paper: Hallynck T, Soep HH, Thomis J, Boelaert
J, Daneels R, Fillastre JP, De Rosa F, Rubinstein E, Hatala M, Spousta J and Dettli L,
Prediction of creatinine clearance from serum creatinine concentration based on lean
body mass. Clinical Pharmacology & Therapeutics 30(3): 414-21, 1981.
Thanks for pointing out this interesting study of Lean Body Mass as a predictor of CPR.
Note however that LBM is NOT the same as IBW. LBM (as described by Hallynck et
al.) is based on the skinfold thickness (at subscapular and biceps sites) and total body
weight. IBW on the other hand uses gender and height i.e. very dierent body properties.
Nick Holford
108
S EC T I O N 15
CVVH (Continuous Venovenus

Hemofiltration)
CVVH
On 19 Mar 1996 at 09:32:05
Our PICU docs are about to start using CVVH (Continuous Venovenus Hemofiltration)
in the unit. Our Pediatric Clinical sta consist of me and 1 part-time sta RPh. I have
only seen the procedure once in a hospital 400+ miles away. Now the questions. 1) How
many of you out there are familiar with CVVH in your present or immediate past institution? 2) How much is the pharmacist involved in the set-up and monitoring of CVVH?
Our docs expect me and our "team" to monitor all drug levels and adjust doses as needed
once CVVH is turned on. 3) Is there any literature out there concerning drug clearance in
CVVH that is not covered by dialysis? Any additional advice/warning would be appreciated.
Robert Aucoin
Baton Rouge, La.
On 22 Mar 1996 at 11:32:38
Their are several forms of this dialysis procedure. CVVH,CVVHD,CAVH,CAVHD. We

have used CVVH,CVVHD most recently at our institution. The sieving coecient can depend on the filter used. In general I will follow the start time, blood flow, dialysis filtration
rate and ultrafiltration rate, and daily fluid removed. Depending on the patients problems,
empiric dosing is done on the limited available literature for CVVH or CAVH sieving coecients. Most of the children requiring CVVHD would be individually unique, making
it even more of a challenge. For those agents that drug levels are available, I will calculate
a clearance rate during the CVVH and adjust accordingly with changes in the dialysis. For
severe infections, aminoglycoside levels are kept between 3-7mg/l, and vancomycin above
109
10-15mg/l (depending on assay error secondary to CDP-1). Some references to help get you
started are:
1. Bressole F et al. Clinical Pharmacokinetics During Continuous Haemofiltration. Clin
Pharmacokinet 1994;26 (6):457-471
2. Armstrong DK et al. Vancomycin and Tobramycin clearance in a n infant during continuous hemofiltration. Annals of Pharmacotherapy 1993; 27:224-227
3. Thomson AH et al. Gentamicin and Vancomycin removal by continuous venovenous hemofiltration. Annals of Pharmacotherapy 1991; 25:127-129.
Willaim Dager, Pharm.D.,FCSHP
Coordinator, Pharmacokinetic Consult Service, UC Davis Medical Center
On 25 Mar 1996 at 09:44:43
Thank you for the info. I'm putting together a packet of info on CVVH that has been
sent to me from around the country. If I can help you with anything, give me a shout.
Robert Aucoin
On 25 Mar 1996 at 09:44:45
I would add:
Reetze-Boroden P, Bohler J, Keller E. Drug dosage in patients during continuous renal replacement therapy. Clin Pharmacokin 1993; 24:367-379.
This article contains a lengthy table of suggestions for dosage adjustments, depending on
the type of continuous therapy that is being used, and organizes the information by drug
class.
110
S EC T I O N 16
Debates in Pharmacokinetics
On 10 May 1996 at 10:15:32
As part of my advanced pharmacokinetics course for students here I require a formal debate of PK "controversies." The purpose is not to win or lose (though that tends to become part of it) but rather to examine papers carefully and come up with reasoned responses to the questions. Below are some of the topics used each year. My request is for
IDEAS ON OTHER TOPICS that I might use. Any suggestions will be appreciated.
DEBATE TOPICS
1.
Pharmacokinetic monitoring services are cost-eective!
2. Theophylline concentrations are useful predictors of eectiveness and safety!

3.
Interpretation of phenytoin concentrations should be based on measurement of unbound drug!
4. Ideal body weight should be used to predict creatinine clearance from serum creatinine!
5.
Large dose, extended interval (sometimes called "once-daily") dosing of aminoglycosides is better than traditional dosing!
6. All patients receiving gentamicin should have troughs less than 2 mg/L to prevent toxicity!
7. Peak concentrations of aminoglycosides are valuable predictors of ecacy!
8. Measuring concentrations of tricyclic antidepressants is necessary to ensure safe and
eective therapy!
9. Vancomycin dosing and pharmacokinetic evaluation should be based on a onecompartment model (rather than two compartment)!
10. There is no need to measure vancomycin concentrations!
111
11. All patients receiving aminoglycosides for more than two days should have concentrations measured!
12. Measuring digoxin concentrations is a waste of time and money!
13. Bayesian analysis improves therapeutic drug monitoring!
14. Neonates do not get toxic on aminoglycosides!
15. Estimates of creatinine clearance from serum creatinine and patient factors is as accurate as measuring creatinine clearance with urine collection!
16. Laboratory assays of drug concentrations are very accurate and can be trusted!
17. The therapeutic range for procainamide is well established and well documented!
18. Aminoglycoside "peak" concentrations should be drawn one-half hour after the end of
a dose infusion and "trough" concentrations should be drawn one-half hour before the
next dose!
19. A panel (three or more) of aminoglycoside concentrations is more accurate than only
measuring a peak/trough! (See Zaske et al.)
20. Pharmacokinetic monitoring of phenytoin is unnecessary - "seat of the pants" dosing
is just as eective!
21. When monitoring lithium concentrations, the blood for measurement should always
be taken approximately 12 hours after a dose!
22. Therapeutic drug monitoring is underutilized for many drugs!
23. Measuring saliva concentrations of drugs oers a reliable approach to therapeutic
monitoring!
24. Accurate phenytoin dosing requires measurement of two steady-state concentrations!
25. Phenytoin dosing should be based on ideal body weight!
26. Aminoglycoside dosing should be based on ideal body weight!
27. Carbamazepine concentrations are useful predictors of eectiveness and safety!
112
On 12 May 1996 at 14:10:11
John:
Let me throw in a suggestion for controversy subjects that will really get the discussion going:
Measurements of drugs in blood only provides data on what happens in the blood. Noninvasive methods are required to measure the time course of drugs at organ and tissue sites.
Professor Walter Wolf, Ph.D.
Director, Pharmacokinetic Imaging Program, Department of Pharmaceutical Sciences,
University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033
On 13 May 1996 at 17:31:48
Are there any FDAers out there or experienced individuals running these types of trials?
If so, I need your opinion.
Is it necessary to analyze placebo samples in open-labeled or blinded studies for all phases
of drug development? If so, would it be acceptable to analyze a fraction of them at random?
Prasad Tata
On 16 May 1996 at 21:57:50
How about debating the pros and cons of detailed multi-compartmental modeling of
pharmacokinetic data as contrasted with classical PKPD modeling?
Another good one might be: Linear models are perfectly adequate for description of pharmacokinetics, and nonlinear models are always a
solution in search of a problem.
Bob Phair.
113
On 19 May 1996 at 21:11:24
How about :
Most kinetic Drug interactions are of theoretical rather than practical importance
Noel E Cranswick
114
S EC T I O N 17
Drug interaction study to role of Cytochrome

P-450 2D6
On 18 Dec 1996 at 11:00:43
We all know for studying cytochrome P-450 2D6 role in drug metabolism it is customary
to study Drug-Quinidine interaction. Due to fluorescent interference of quinidine with
the study drug, I am considering to use Ajmalicine (reported Ki = 0.014) or prodipine (Ki
= 0.0048). Can somebody share their clinical or analytical experiences with me.
Prasad Tata, Ph.D.
On 19 Dec 1996 at 11:00:15
In response to the 2D6 question- A lot of work has been done using dextromethorphan as
a marker for 2D6. Perhaps that could be an alternative agent you could use.
Kristen Jones, PharmD, BCPS
Assistant Professor, Campbell University, Buies Creek, NC 27506
On 23 Dec 1996 at 14:11:13
There is a paper in the Journal of Medicinal Chemistry which appeared in

1993 (Vol.36, issue 9, pages 1136-45) entitled "development of a
pharmacophore for inhibition of human liver cytochrome P450 2D6:
molecular modeling and inhibition studies" by Strobl GR et al, that you
may find informative (I know this does not answer your question directly!).
Rajesh Krishna
115
S EC T I O N 18
Eect of Dosing Vehicle on Pharmacokinetics

On 31 Aug 1996 at 22:43:21
I would like to know the eect of dosing vehicle used to intravenous administration on
pharmacokinetics (plasma concentration). For example, when a drug is administrated as
saline or PEG-400 solution, whether would the pharmacokinetics of drug be same between the two vehicles.
Teruaki Okuda
On 2 Sep 1996 at 22:50:02
Since the route of administration is intravenous (avoiding the Absorption phase) my initial
thought isn't so much kinetics vs. chemistry & toxicology. A drug that's stable in saline
wouldn't really need to be administered in PEG-400 would it?
Richard Molitor, R.Ph.
Seattle, Wa
On 2 Sep 1996 at 22:50:07
The "safe" answer to your question is: if the vehicle does not (1) change the dissociation of
the drug through pH eects, (2) dose not eect binding of the drug (e.g., to exipients in
the vehicle), (3) does not unduly alter the initial concentration of drug in the bolus, and (4)
the vehicle has no vascular eects of its own, then the initial absorption and ultimate
plasma concentration curves should not vary noticeably between vehicles, at least within
the typical variance associated with dosing and sampling.
Dr. David S. Farrier
Summit Research Services, 1374 Hillcrest Drive, Ashland, OH 44805
116
S EC T I O N 19
Felbamate - gabapentin Interaction

On 24 Jul 1996 at 11:58:04
I Like to participate.
Therapeutic Window (TW) for Felbamate.
This is part of a large study evaluating dose-response curve for felbamate in mono-therapy
and poly-pharmacy for the treatment of refractory seizure. TW was found to be 50-110mg/
l. Data submitted for publication at the Neurology. Let me know if you are interested, so I
can prepare to present it at the ACCP.
Gamal Hussein, Pharm.D. and Allan Troupin, M.D.
Northeast Louisana University, College of Pharmacy and LSU-Medical School, Dept. of
Neurology
On 25 Jul 1996 at 12:52:13
Felbamate is now used only in rare cases. I imagine there very little interest in it at present.. However, a poster and an abstract would be appropriate.
Dr.Anaizi
On 27 Jul 1996 at 11:46:23
Felbamate article "Therapeutic Windows" was accepted to the Epilepsy. Many Children
still on felbamate. I just discovered a new drug interaction where Gabapentin decreases felbamat clearance by >50%. This was accepted at the "Neurology". Anyway, you'r right with
regard to the little interest on the subject. I am just trying to HELP.
I have an excellent Seizure Clinic here in Charity hospital, A pharmacist and a physician
see the patient&family in the same time, this may serve as role model for other individuals
interested in providing progressive pharmaceutical service with a focus on antiepilepsy
117
drugs/pharmacokinetics and outpatient clinics. I can discuss our clinic, its evolution and
impact on patient outcome.
Other potential project is Rasmusen Encephalitis. It is a rare disorder of uncontroled seizure, A case report and literature review may be helpful, if you decide so. Most of these patients are in the pediatric age group. phenobarbital coma is the first step adter the failure
of available anticonvulsant which is commonly encountered. The treatment is still unknown, with plasmaphoresis, IVIG and immunosupressants as options. this subject may
generate a good debate for those interested in seizure control. let me know if I can be of
any help.
Gamal Hussein, Pharm.D.
On 29 Jul 1996 at 11:48:30
Dear Hussain,
I find your observation regarding felbamate <-> gabapentin interaction very interesting. I
would be very interested in any observations you might have regarding the nature of the
interaction. My understanding of the pharmacokinetics of these two antiepileptic drugs is
that while felbamate is metabolized by the liver, gabapentin is not. Indeed, gabapentin is
entirely dependent on glomerular filtration for its elimination; its clearance appears to be
directly proportional to the GFR. What I find curious about gabapentin is that it does not
appear to be reabsorbed to any significant extent by the renal (proximal) tubules, although
it is known to be absorbed from the small intestine by a Na-dependent co-transport system, which is normally responsible for the absorption of aminoacids. A similar aminoacids
transport system is known to exist in the proximal tubule.
N Anaizi
On 30 Jul 1996 at 12:26:01, GHussein.at.aol.com sent the message

Notes in gabapentin-felbamate interaction:
118
Felbamate's elimination by the kidney is known, but not appreciated, since it is about
50%. My best speculation is that gabapentin competes at the molecular level for renal excretion of felbamate rather than competition/induction of hepatic metabolism. We have
not yet evaluated other data that will define the potential eect of felbamate on the excretion of gabapentin, a possible correlate of the data discovered by my group. These data
were accepted for publication at "Neurology".
Gamal Hussein, Pharm.D.
119
S EC T I O N 20
Fenoterol Pharmacokinetics
On 14 Mar 1996 at 11:00:38
I need information, data (oral resorption, plasma concentration, plasma protein bond, renal excretion,...) about "fenoterol", used for tocolysis/inhibition of premature labor.
Walter-R. Kaempf M.D.
On 15 Mar 1996 at 11:54:03
Some information (scanty, but with further citations) is in

McCombe J. 1995 Update on tocolytic therapy. Ann Pharmacother 29, p515-22.
Dept. of Pharmacy, Creek & District Hospital, Dawson Creek, BC Canada
120
S EC T I O N 21
Flucytosine Pharmacokinetics
On 23 Oct 1996 at 10:41:10
Is there someone out there who has experience with dosing of flucytosine? From what I
know and have read, peak levels >125 mg/L are toxic (bone marrow suppression and hepatotoxicity) and those <50 mg/L would be at risk of developing resistance. We see very few
patients here at DHMC who receive 5-FC (and amphotericin) but always seem to have
problems with their regimens, mostly because we mail out the drug samples and do not
have results back until 48-72 hours later.
Clinical Pharmacist, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756
On 24 Oct 1996 at 10:41:31
The data linking serum concentrations of 5FC with ecacy or toxicity are, as for many
drugs, anecdotal. Generally we try to maintain serum concentrations (we usually draw a
random sample midway through the dosing interval) of around 70-80 mcg/mL.
One should continue to monitor platelet and WBC counts, even when concentrations are
within the "normal" range. Some literature suggests that 5FC is converted to 5FU by intestinal bacteria/yeasts which contain cytosine deaminase, rather than this conversion occurring in plasma. Therefore, factors other than serum 5FC concentration (e.g., duration of
therapy) may be more important vis a vis toxicity.
Steven C. Ebert, Pharm.D., FCCP
Clinical Specialist, Infectious Diseases, Clinical Associate Professor of Pharmacy, Department of Pharmacy, Meriter Hospital, 202 S. Park Street, Madison, WI 53715
121
S EC T I O N 22
General Pharmacodynamic Reference Book

On 5 Dec 1996 at 10:50:37
Does anyone has good references on principles, design, responses definition, modelling
and statistical analyses of pharmacodynamic studies.
Francois Vandenhende
Statistician, Lilly Research Laboratories, MSG - Belgium
On 8 Dec 1996 at 18:29:19
There are several texts in pharmaceutical statistics. For clinical trials or otherwise, a couple of good books are:
1.
Planning pharmaceutical clinical trials: basic statistical principles. William M. Wooding
2. Statistical methodology in the pharmaceutical sciences. Donald A. Berry.

Rajesh Krishna
On 8 Dec 1996 at 18:31:05
You might want to look at: Van Boxtel et al. "The In Vivo Study of Drug Action". Elsevier
1992. This book attempted to cover most of what you ask for but of course it is now 5
years old. Principles havent changed much however.
Nick Holford
Dept Pharmacology & Clinical Pharmacology. University of Auckland, Private Bag 92019,
122
S EC T I O N 23
Gentamicin in endocarditis
On 27 May 1996 16:31:53
Summary:
A colleague in hospital pharmacy has asked me to inquire whether others have experience/
information on departures from recommended dosage adjustments for gentamicin in patients who are being treated for endocarditis.
Details:
In this case, a patient has renal failure and is being dosed with gentamicin 80 mg at 8 h intervals giving high trough values (2.7 mg/L) and low peak values (5 mg/L).
The standard procedure would be to lengthen the interval between doses, so that the desirable trough approaches zero and the peak is 12-15 mg/L.
However, the infectious disease medical specialist believes that a continuous low drug
level will give the best result in endocarditis.
We would be pleased to hear of anything specific which either suports or refutes this view.
Stuart McLean, MPharm, PhD
School of Pharmacy, University of Tasmania, GPO Box 252C, Hobart 7001, Australia
On 28 May 1996 at 12:30:27
1.
What is the organism?
2. What are the other antibiotics being used?

3.
Is ampicillin (or another beta-lactam) being used, and is it being
given by continuous infusion?

123
On 28 May 1996 at 12:30:33
Based on my past experience, high peaks are important to ensure penetration of gentamicin into the vegetation. One previous patient that I was involved in the treatment received tobramycin at a dose to produce peaks of 15 mg/L and troughs of <1 mg/L. for a
Pseudomonas aeruginosa endocarditis. The patient was successfully treated, although 2
courses of therapy were required without nephrotoxicity. With the elevated trough levels,
it is unlikely that the patient will be able to complete the required 6-8 weeks of therapy
with gentamicin due to nephrotoxicity. Depending on the age of the patient, nephrotoxicity is likely to be seen starting at 5 days into the therapy. The question is one of is it more
important to complete the duration of therapy without nephrotoxicity or have a short
course due to high troughs with resultant nephrotoxicity with limited penetration into the
vegetation. Since there is no blood flow to the valves except the surrounding blood in the
heart, high peaks to facilitate diusion into the vegetation seem more important to me.
Michael Burton
On 29 May 1996 at 10:29:17
As Mike Burton has noted, the type of bacterium causing the endocarditis may influence
the importance of serum concentration monitoring. For Pseudomonas endocarditis, I
agree that high concentrations (tobramycin peaks of 10-14 mcg/mL) are best, with troughs
<1 mcg/mL. On the other hand, for staphylococcal, alpha-streptococcal, or enterococcal
endocarditis, lower peaks (5 mcg/mL or less) with troughs <1 are probably sucient. SCE
Steve Ebert
On 31 May 1996 at 10:59:38
In response to follow-up questions from Randy Trinkle:

1. What is the organism?
Unknown until valve is removed and cultured.

2. What are the other antibiotics being used?
124
Vancomycin, initially I.V. 500 mg 12 hourly, now 1 g daily.

3 Is ampicillin (or another beta-lactam) being used, and is it being given by continuous infusion?
No
Stuart McLean, MPharm, PhD
School of Pharmacy, University of Tasmania, GPO Box 252C, Hobart 7001 Australia
125
S EC T I O N 24
Guidelines for Furosemide IV push

On 21 Oct 1996 at 16:59:11
I am posting this for the Clinical Pharmacist at our hospital. I hope someone can provide
us with some help.
Are there any guidelines published for furosemide IV push administration? The manufacturer states that 20-80 mg can be given IV push over 1 to 2 minutes and that "high dose"
parenteral therapy should be administered as a controlled intravenous infusion at a rate of
not greater than 4 mg/min. Is it safe to give furosemide undiluted in doses > 100mg IV
push over 1- 2 minutes which would exceed 40 mg/min?
We have not found an answer in a search of the literature.
B. Miers
Health Science Librarian, Methodist Medical Ctr., Peoria, IL
On 22 Oct 1996 at 12:07:51
The main problem associated with furosemide when given IV push is ototoxicity. This appears to occur particularly as a result of high serum peaks of loop diuretics (ethacrynic
acid >> furosemide > bumetinide). Here are some "rules" that I try observe when using furosemide: 1- Maximum rate of iv push = 40 mg/min (no need for dilution) 2- Dose may be
doubled every 2 hrs until adequate response is achieved. 3- The individual dose should not
exceed 160 mg. 4- Total daily (iv) load should not exceed 800 mg (that is five 160-mg
doses). 5- Oral dose = 2 x iv dose (bioavailability is about 60%)
Furosemide is sometimes given as a bolus followed by continuous iv infusion (diluted appropriately) at the rate of 0.05 - 0.5 mg/kg/hr (to achieve and maintain a serum level of 1-2
mg/L). This method of administration may reduce the risk of ototoxicity, but it does not
appear to enhance the diuretic response.
126
I hope this information is useful!

Needless to say that I assume no legal responsibility.
N. Anaizi, PhD RPh, Univ of Rochester Med Center
On 23 Oct 1996 at 10:41:32
Thanks very much for the useful information on furosemide guidelines. It was greatly appreciated!
B.Miers, Methodist Med. Ctr., Peoria, IL
On 23 Oct 1996 at 10:41:59
I tend to disagree with Dr. N. Anaizi that the individual dose should not exceed 160 mg.
Many patients with severe renal failure may not adequately respond to this dose, in which
case the dose needs to be doubled. For a wonderful discussion of diuretic resistance, I
highly recommend:
Brater DC. 1993 Resistance to diuretics: mechanisms and clinical implications. Adv Nephrol Necker Hosp 22, p349-69.
Assistant Professor, Department of Pharmacy Practice, College of Pharmacy, University of
On 24 Oct 1996 at 10:40:39
The issue of diuretic resistance raised by Dr. Atashkadi is a more specific one. I was addressing general guidelines for the more common, inpatient use of loop diuretics. On a
few occasions we have used furo doses in excess of 200 mg in pts with oliguric RF. In most
of these cases furo was used in combination with chlorthiazide to block Na reabsorption
at the more distal sites of the nephron.
127
A comprehensive discussion of the clinical pharmacology of diuretics may be found in section V of Messerli's Cardiovascular Drug Therapy published by Sauders (2nd edition,
'96)
N. Anaizi
128
S EC T I O N 25
Ketoconazole - Cytochrome P-450 Inhibition

On 25 Jul 1996 at 14:13:43
My understanding is Ketoconazole is a Non Specific inhibitor of Cytochrome P-450 (according to the original papers published by Jansseen Pharmaceutica). It is a non specific inhibitor with somewhat more anity towards, CYP-450 3A4. In recent times I started seeing several papers probing the metabolic pathway of drug candidates stating because the
metabolism of Drug X is inhibited by ketoconazole so Drug X metabolism is mediated by
CYP-450 3A4. In my opinion this type of observations are ACCEPTING A FALSE HYPOTHESIS (TYPE II ERROR ??).
If we want to test whether a particular drug is metabolized by 3A4 or not the best way is
to see the eect of induction by Dexamethasone and also looking for Inhibition of metabolism by Gestodene or Norethindrone which are known to be Very specific inhibitors
for CYP-450 3A4.
Can someone throw some light on this aspect.
Prasad Tata, Ph.D.
Department of Pharmacokinetics, Otsuka America Pharmaceutical, Inc., 2440, Research
Blvd., Rockville, MD 20850
On 26 Jul 1996 at 10:43:42
Just wanted to add that Rifampicin is beleived to be a most potent inducer of CYP3A4
subfamily mRNA. Other inducers include phenobarbitol and Pregnenolone 16alphacarbonitrile.
Both Ketoconazole and gestodene, albeit very potent, are a non-selective inhibitor of
CYP3A4. Troleandomycin is presumed to be a very specific inhibitor of CYP3A4.
129
So, Rifampicin and Troleandomycin can be used to identify the cytochrome P4503A4 isoform.
Additionally, the purified CYP3A4 (not easily available) can also be used.
FYI, I maintain a PK/PD/Biopharmaceutics Home Page that also has a table of dierent
P450 isoforms, some substrates, inducers and inhibitors. The URL is given in my attached
signature file.
G Krishna
http://grin.vcu.edu/~gkrishna/PK/pk.html
On 30 Jul 1996 at 12:26:02
Using induced microsomes to determine the primary cytochrome P450 responsible for metabolizing a substrate is questionable. Upon induction, you can markedly change the relative composition of specific P450s in the liver - some non-constitutive enzymes will beexpressed after induction, while some constitutive P450s will be suppressed. Hence, using induced microsomes may lead to an inaccurate conclusion as to the primary P450 responsible for metabolizing a substrate. We found this to be the case with dapsone (see Vage C &
Svensson CK. Drug Metab Dispos 22:572, 1994.). It is also important to recognize that substrate concentration can influence which P450 predominates in the metabolism of a substrate. Hence, the best way to make this assessment is via a battery of experiments.
Craig K. Svensson, Pharm.D., Ph.D.
Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48202
USA
http://wizard.pharm.wayne.edu/svenss.html
On 31 Jul 1996 at 12:31:04
Dr. Swanson,
Your observation that it is better to test inhibition reactions in constituent stage is a good
time tested idea. However to quickly pin point what isoform is responsible for the metabo130
lism of Drug X many people used induction of selective isoform and looking for corresponding increase in a particular metabolite formation (metabolic pathway) and subsequent inhibition by a selective inhibitor. This strategy provides quick way of getting a feel
on the major metabolic pathways based on these initial experiments further experiments
can be planned for further probing the metabolic profile of a drug candidate.
My question is whether we can classify Ketoconazole as a Specific inhibitor of CYP 3A4
or it is a non specific inhibitor of CYP-450.
Prasad Tata
131
S EC T I O N 26
Once Daily Administration - Aminoglycoside

On 8 May 1996 at 10:40:49
Our hospital has been using od aminoglycosides for several months. The dosage range is
5-7mg/kg/day (for gent and tobra).
Comparison studies with conventional q8h administration found similar ecacy /c no
greater toxicity. (This stu is on MEDLINE.)
The putative clinical advantage relies on a sequence of events when susceptible bacteria
are exposed to an aminoglycoside. Since the drug has an intracellular mechanism, it requires some sort of transport into a bacterium. A conventional trough concentration appears to be high enough to down regulate this transport, making bacteria less susceptible.
Allowing the concentration to drop over 8 half-lives (eectively to zero), which is what a
dose/24h amounts to, allows bacteria to "recover" the transport mechanism. In addition,
some drug binds to extra-membrane bacterial structures, and as extra-bacterial drug
concentration drops, bound drug becomes unbound (it's a reversible binding event with a
low enough anity constant to make this possible). This unbound drug is then taken up
by bacteria to eect a kill. This last bit is also an explanation proposed for the 'postantibiotic eect' exhibited by the aminoglycosides.
Even if there doesn't turn out to be a greater clinical eectiveness with od dosing, there
are other advantages. We now see more patients being treated on an out-patient basis in
our ER, since they only have to come in once a day. There's also the reduced cost of administration for in-patients, with nurses preparing and hanging one dose a day rather than
three, plus no more gent assays. After all, what would you be measuring--that there's nothing there after 24 hours? The assay that *is* done is serum Cr, just so you know how the
patient's kidneys are holding up, and if their renal function is such that you can assume a
normal half-life. If their Cr is high, give the gent every 36 or 48 hours.
132
On 8 May 1996 at 10:40:47
For Once-daily aminoglycoside dosing:

Two references are:
Nicolau,DP, Freeman,CD, Belleveau,PB, et al. 1995 Experience with a
Once-Daily Aminoglycoside Program Administered to 2,184 Adult Patients.
Antimicrobial Agents and Chemotherapy, 39(3), 650-655.
Gilbert, DN. 1991 Once-Daily aminoglycoside therapy. Antimicrobial Agents
and Chemotherapy, 35(3), 399-405.
The dose given is usually 6 to7 mg/kg for Gentamicin or Tobramycin, and the frequency is
adjusted based on a random level as shown in the nomogram in Nicolau's paper. I am not
aware of a paper describing once daily dosing in pediatrics, and we use conventional dosing (adjusted by levels) for patients with renal failure or deep tissue infections (osteo, or endocarditis).
On 8 May 1996 at 10:40:54
I have just recently seen a posting to this group referring to ODA. There seemed some
concern over the references and pharmacists that use this protocol. The definitive article
describing this practice was written by Hartford Hospital and is available in several journals. At the hospital I work at the pharmacists monitor the aminoglycoside therapy for patients on the ODA protocol. Those pharmacists have demonstrated their capability by
passing a stringent pharmacokinetic examination and demonstrating the clinical ability. In
short the ODA protocol is as follows. Gent or Tobra are doses as 7 mg / kg on ideal body
weight(given over 1 hr)( ideal weight = 50kg + 2.3kg x height in inches over 5 foot for males
(females are 45kg + 2.3kg/inch > 5foot))obese individuals( 30% > ideal wt) are dosed as ideal
body weight + 0.4 x excess wt over ideal). After this initial dose a random level is obtained
from 6 - 14 hrs after the start of the infusion. This level is plotted on the aminoglycoside
nomogram to determine the dosing frequency (q24 , q36, or q48 hrs). This level is repeated
in 5 days or if clinically necessary. Some patients are excluded from the protocol ie preg133
nancy, renal diaylsis, burn patients, severe ascites, cystic fibrosis, and endocarditis. Some of
the doses I have seen are from 280mg to 680mg ivb q24 hrs. The reasoning behind the protocol is to have the trough level fall below 0.4mcg/ml about 4 hrs before the next dose. (remember aminoglycosides exhibit a post antibiotic eect) Clinical experience shows that
the aminoglycoside level that provides poor outcomes is the trough level > 2.0 mcg/ml.
The higher peak levels allow for aminoglycosides to achieve a better antimicrobal eect
than traditional dosing. Pseudmonas infections can be treated with this regimen. Hope
this helps
TGUSCHEL
On 9 May 1996 at 10:06:56

In addition, some drug binds to extra-membrane bacterial structures, and as extrabacterial drug concentration drops, bound drug becomes unbound (it's a reversible binding event with a low enough affinity constant to make this possible). This unbound
drug is then taken up by bacteria to effect a kill.
What is an extra-membrane bacterial stucture? Is this part of the bacterium? Those hairy
bits that some bacteria have?
So are you saying that the kinetics of unbound drug close to the eect site are determined
by binding to the bacterium itself ? Is there any direct experimental support for this or is
hypothesis only?
... plus no more gent assays. After all, what would you be measuring--that there's
nothing there after 24 hours? The assay that *is* done is serum Cr, just so you know
how the patient's kidneys are holding up, and if their renal function is such that you
can assume a normal half-life. If their Cr is high, give the gent every 36 or 48
hours.
Nothing like closing the stable door after the horse has bolted!
PLEASE consider measuring the gent concs. They are a more sensitive marker of renal
function changes (Thalf of gent is half that of creatinine). Plus you can use the gent concs
to adjust the dose BEFORE the patient's renal function deteriorates.
Measuring gent concs at 1 and 8 hours after the od dose will give readily measurable concs
and if your lab is up to scratch you will have the results back before the next dose is due.
Nick Holford
134
On 9 May 1996 at 10:06:58
On the Once-daily aminoglycoside story

The blokes at Clinical Pharmacology in Christchurch (NZ) have been the southern hemisphere players in this game fro some time.
This team have published some clear guidelines and a suggested approach
Evan Begg, Murray Barclay, Steve Duul. 1995 A suggested approach to once-daily aminoglycoside dosing Brit J Clin Pharmacol, 39, 605-609
Barclay, Duul, Begg & Buttimore. 1995 Experience of once-daily aminoglycoside dosing
using a target area under the concentration-time curve. Aust NZ J Med 25, 230-235
There has also been a meta-analysis looking at some of the published data
Galloe et al. 1995 Aminoglycosides: single or multiple daily dosing? A meta-analysis on ecacy and safety Eur J Clin Pharmacol, 48, 39-43
Andrew McLachlan
Dept Pharmacy, Uni of Sydney, NSW 2006 Australia
On 9 May 1996 at 13:58:32
I'd like to respond and echo some of Nick's comments re: ODA.
Actually three meta-analyses have been published- one in Lancet (BMJ?), another in Ann
Intern Med, and another in J Antimicrob Chemother. What is interesting is that the papers all have slightly dierent conclusions.
The "definitive paper" written by the Hartford group is largely anecdotal, i.e., "this is what
we did, and it seemed to work". The mean duration of therapy was 2-3 days. The authors
cannot, when prompted, defend the method(s) used to determine the serum
concentration nomogram used. Others who have adopted this method have had problems
135
with toxicity. 7 mg/kg dose is designed to achieve higher peak:MIC for Pseudomonas--why not use tobramycin?
Integration of concentration-eect (bactericidal rate) relationship for aminoglycosides implies that net kill should reflect AUC, not peak. This is why most studies show no dierence (the Prins paper was not a randomized study). ODA will likely be more eective if
only bacteria with high (>2 mcg/mL) MICs are included.
I agree one serum concentration would be appropriate in patients who would traditionally
be dosed q 8-12h. We use a 5 hr post dose to estimate AUC (least biased time point based
on optimal sampling theory). In patients with poor renal function, we obtain peak/trough
as traditionally is done.
We rarely used ODA outside of ICU and home/ambulatory patients. We stratify maximal
daily dose (3-6 mg/kg/d) by estimated CrCl and disease severity. On the other hand, we do
not use 8h interval, but instead go right to q 12h. We average 0.7 serum concentrations/
course (mean 5d) and out nephrotoxicity rate is 2.8%.
Steve Ebert
On 28 May 1996 at 12:30:30
I apologize for raising an issue which has been discussed extensively in the not too distant
past.
My question is whether there are literature data (or personal experiences) to support the
use of ODA in patients with chemotherapy induced neutropenic sepsis, where overwhelming gram -ve septicaemia can develop rapidly in the absence of appropriate antibiotic therapy.
Duncan Jodrell
Senior Lecturer in Medical Oncology
136
On 29 May 1996 at 10:29:14
There wasn't any literature on once daily aminoglycosides in febrile neutropenia when I recently searched. We've been utilizing it in our chemotherapy-induced neutropenia patients (both inpatient and outpatient management), but counts return quickly to normal
(we also use filgrastim) so I'm not sure this is a true test. Our physicians and nurses like it.
We have relatively limited experience in AML patients s/p chemotherapy, however, it appears to be no dierent from conventional dosing. Our experience with impaired renal
function (ie dosing q48 hours) is also very limited. Usually, we do not use it as monotherapy against gram negative organisms, and we have very few resistant gram negative organisms.
Dianne M. Brundage, Pharm.D., BCPS
Methodist Hospital Pharmacy, 6500 Excelsior Blvd, Minneapolis, MN 55426
On 29 May 1996 at 10:29:16
The largest published study was authored by the EORTC and published in Annals of Internal Medicine, around 1992-3 or so. It compared ODA plus once-daily ceftriaxone with 8hourly amikacin and ceftazidime. No dierences in ecacy noted. A delay in onset of
nephrotoxicity was observed in ODA group. Steve Ebert
On 31 May 1996 at 10:59:39
Hi Duncan,
The following very recent paper might be of some interest - perhaps you have seen it already.
R Hatala, T Dinh, DJ Cook Once-daily aminoglycoside dosing in immunocompetent
adults: A meta-analysis, Annals of Internal Medicine 124, 8 (APR 15 1996) 717
Gregory Peterson
Senior Lecturer, Tasmanian School of Pharmacy, University of Tasmania GPO Box 252C,
Hobart, TAS, 7001 AUSTRALIA
137
On 29 May 1996 at 10:29:15
The use of pulse dosing of aminoglycosides in neutropenic patients has yet to be investigated in humans. Studies on neutropenic rats suggest that the "post antibiotic eect" may
be considerably shorter in neutropenia. The implication is that with pulse dosing neutropenic pts would be "unprotected" during the terminal portion of the dosing interval.
These findings led to the notion that neutropenic patients should be excluded from ODA
dosing programs. To date I know of no clinical study that addressed this issue specifically.
However, it is very likely that at least one is going on now. By the way, these same formal
dosing programs exclude pts with endocaditis and all instances in which the aminoglycoside is used for its synergistic eect together with a beta-lactam.
Nasr Anaizi, PhD, RPh
138
S EC T I O N 27
Oleic acid and Lymph

On 7 Feb 1996 at 11:28:28
I am a research student at the University of Bradford (UK), and intend to investigate how
oleic acid alters the bioavailability of drugs that have a high hepatic first pass metabolism,
e.g. propranolol, metoprolol, felodipine. I am in the pharmaceutical technology dept., so
am concentrating on the formulation aspect of drug delivery.
Work with propranolol and oleic acid suggests increased lymphatic transport of the drug
(e.g.Barnwell, Int J Pharm 1992) but considering propranolols' moderate lipophilicity (logP
o/w = 3) this seems doubtful. Any thoughts?
I would be grateful for any comments, advice, constructive criticism concerning oleic acids possible eects on bioavailability.
Kieran Crowley
On 12 Feb 1996 at 11:25:19
What was the evidence presented in that article for lymphatic transport?
J Paul
On 13 Feb 1996 at 09:58:08

What was the evidence presented in that article for lymphatic transport?
Lymphatic cannulation.
Chetan Lathiac
139
S EC T I O N 28
Preclinical Pharmacokinetics
On 7 Oct 1996 at 11:18:31
I have just arrived to PK field, working in preclinical studies. I am trying to manage data
and statistics when comparing bioavailability data obtained from independent animals
(one point, one animal). I have only found a method of calculating and comparing AUC
obtained in this way from Shoenwald et al. I'd appreciate any help in how to deal with statistics in bioequivalence studies when a curve is obtained from dierent animals ending
with a curve made of medium values but not a 'medium curve'
Carmen
On 7 Oct 1996 at 18:01:55

calculation of bioavailability one point per animal...
Was each animal given the same dose and was that dose expressed per kg body weight?
Were data collected after both intravenous and oral doses or did you use some relative
standard? What are the units of measurement of your individual data samples? Do you
have body weights or plasma volumes for the individual animals? Unless all the animals are
the same or nearly the same size, it may be useful to normalize the data set before
calculating the AUC. If the dose was given per kg, this normalization may already be built
into your data set.
You can assign statistical weight to the data based on your knowledge of the measurement
error. Then you can fit the data to a sum of exponentials, or to a compartmental model, or
use a "non-compartmental" approach as described by (for example) Gibaldi, M., Biopharmaceutics and Clinical Pharmacokinetics, 4th ed., Lea and Feibiger, 1991.
As with all AUC measurements, you will have to choose some estimate of the slowest exponential to extrapolate to t = infinity. For this reason, it is always desirable to have data as
far out in time as possible.
140
Now, when you do your least squares fit you will get point estimates for your AUCs and
you will get coecients of variation based on your estimate of measurement error. For this
part of the work, my favorite software is SAAM II, but there are many other capable packages.
Robert D Phair
BioInformatics Services
On 8 Oct 1996 at 12:11:09
Recent article by Ette et al. (J. Pharmacokinet. Biopharm. 1995, 23, 551) may help.
Janssen Research Foundation, Clinical Pharmacokinetics, B-2340 Beerse Belgium
141
S EC T I O N 29
Pharmacokinetic Software
On 2 Dec 1996 at 10:35:37
Several people have posted asking me to list the references I received and the programs on
my evaluation list. Here they are.
Please note that the list is in no particular order, and not all programs are necessarily
equivalent - this is just what I got back from the group. I'm not sure if it's kosher to include Email addresses, but have assumed that if someone is providing a product they don't
mind being contacted... [my apologies if this is not the case]
The best all-around source for this information is still
http://www.pharmpk.com/soft.html
but I was only interested in IBM-PC-WIN3.x-MSExcel-compatible programs, which is a
much smaller window.
1.
T.D.M.S.
2. MultiForte & Boomer from David Bourne [[email protected]][love that kangaroo!]

3.
"Fit-Regression" from WindowChem Software [www.windowchem.com], a product

which we purchased as an Excel add-on]
4. NCOMP from Paul Laub [[email protected]]

5.
PKAnalyst from Micromath [www.micromath.com] - they also have a product called

Scientist with PK add-ons, but it doesn't look too dierent from PKAnalyst based on
the demos I downloaded from their site
6. WinNonlin from Pharsight

[http://www.pharsight.com/products/prod_winnonlin_home.php]. This product follows on from PCNONLIN, which I have used before.
7. SAAM from NIH [www-saam.nci.nih.gov/saam.htm]
142
There are a few other leads I haven't followed up on yet:

ACSL BioMed and Optimize at www.mga.com
Kinetica [by Simed] at www.bioscience.com
PCMODFIT [contact Alan Thawley, alan.-a-.artpac.demon.co.uk]
METABASE & PK SOLUTIONS at www.bright.net/~dfarrier/index.html
Prices of the above range from zero to ridiculous! I have not yet looked at them all, so I
have no comments to make on any. Once again, my thanks to everyone who responded,
and I hope all of my transcriptions and citations are accurate.
Adrienne Stevenson
Ottawa, Canada
On 3 Dec 1996 at 15:27:06
Thanks for the list of PK programs you are evaluating. Since you specifically mention Excel, you might consider looking at PKPD Tools for Excel with XLMEM. This is a public
domain Excel spreadsheet by Charles Minto and Thomas Schnider. You can find it on my
WWW site: http://pkpd.icon.palo-alto.med.va.gov
One interesting aspect to this is the implementation of mixed eect modeling, using the
NONMEM objective function (first order approximation), in a dynamic link library accessible to Excel. The function returns the same values as all of the NONMEM test sets,
with comparable execution times (the code is compiled). However, it is limited to the series of models implemented in PKPD tools, and thus has neither the flexibility nor the
more recent objective functions (e.g., conditional estimation) implemented in NONMEM. At present, it is a prototype of a more complete population analysis tool with Excel
that Drs. Minto and Schnider hope to build.
PKPD Tools should be interesting. It is still evolving, with major updates every 6-8
months, as Drs. Minto and Schnider have time to make additions.
Steve Shafer
143
On 3 Dec 1996 at 15:37:34
SAAM from the NIH is a good package that has been in use for decades, but my actual kinetics software recommendation to Adrienne Stevenson was for SAAM II with an intuitive graphical user interface and a bunch of hotshot peer-reviewed optimizer algorithms
and flexible weighting schemes. You can find out more about SAAM II from the Epsilon
Group [http://tegvirginia.com/solutions/saam-ii/]
Robert D Phair PhD
http://www.webcom.com/rphair
On 5 Dec 1996 at 10:33:39
Dear all,
I am interested in getting a moderately priced PK analysis package which is Windows compatible. I have seen the demo versions of Scientist and PKanalyst from Micromath. They
appear slightly similar although my understanding is that in Scientist there is greater flexibility for the model equations (simultaneous dierential, Laplace etc) as well as the possibility of fitting simultaneously data of other metabolites or concentrations in other compartments which would be useful for my work. I would like to know if anyone out there
has purchased and used either of these packages and whether they found significant hickups. Any comparisons of these and better/worse PK packages would be welcome. In the
past, I have done my fitting with a combination of Sigmaplot, the free listing of Yamaoka
K et al J. Pharmacobio-Dynam 4:879-885, 1981, and the method of using EXCEL for nonlinear curve fitting described by Bowen and Jerman, TIPS 16:413-417, 1995.
Sigmaplot is OK for simple equations, the Yamaoka program is extremely versatile and
with some re-writing can load/save info to disc (however it is a B/W dinosaur) and the EXCEL method is good for enzyme, cytotoxicity and PD work but is out of the question for
serious PK work. Time to go upmarket and get something more presentable.
Laurent P Rivory
Department of Medicine, University of Queensland, Princess Alexandra Hospital, Ipswich
Rd, Woolloongabba 4102, QLD, Australia
144
On 6 Dec 1996 at 10:32:30
All the programs you mentioned are a variation on the theme of curve fitting. The short
coming as I see it (and I hope others might share their own viewpoints on this) is that programs such as these give good equations and curve fits but provide little in the way of useful PK parameters. Typically they give little more than the AUC, half-life and lag-time. On
the other hand, when one surveys, for example, Drug Metabolism and Disposition, the
vast majority of papers dealing with pharmacokinetics provide tables which include these
and other PK parameters (such as the Vd, Cl, MRT, AUMC, etc.) as their primary results.
Typically, these results are all based on non-compartmental assumptions. I tabulated the
contents of 2 years of DMP issues to arrive at this fact. It appears that compartmentalists
need equations, but practitioners need parameters. To fill the void in software, I developed a program called PK Solutions. It runs in Excel and is automated with VBA procedures. It calculates about 25 parameters for blood levels obtained after single oral or iv bolus and predicts an additional 25 steady state parameters based on multiple dosing. It provides curve stripping and/or Excel Solver-based curve fitting of time-concentration data,
or one can supply exponential terms derived from other software (i.e., curve fitting software).
Summit Research Services, 1374 Hillcrest Drive, Ashland, OH 44805 USA
On 6 Dec 1996 at 10:34:28
About Laurent Rivory's question about PK analysis packages:

I suggest considering ADAPT II, the PKPD simulation and fitting program written by
DZ D'Argenio and A Schumitzky and available at little or no cost from the Biomedical
Simulations Resource at the University of Southern California. I have heard that a Windows version of ADAPT II is nearing completion; in the meantime an excellent DOS version exists and has a devoted following (myself included).
Advantages of ADAPT II:
1.
145
Enormous flexibility, in that you write the equations or dierential equations describing the system as well as the variance function describing the presence of noise or error.
2. Statistical features not found in other packages such as fitting using Bayesian priors as
well as support for designing optimal sampling.
3.
The program comes as well documented FORTRAN 77 source code, so that if you absolutely have to, you can "look under the hood" and find out how the program works.
4. Track record - the program has been around since 1979 and has many users worldwide;
the authors at USC regularly hold conferences or training courses on ADAPT (as they
did last May).
Disadvantages of ADAPT II:
1.
Enormous flexibility - maybe too much for someone learning pharmacokinetics. Additionally, flexibility assumes basic knowledge of writing FORTRAN code as well as
compiling and linking FORTRAN programs.
2. Requires a FORTRAN compiler, so that while ADAPT II is free (at least to academic
users), the compiler is not. But in a lab where lots of number crunching is going on, a
FORTRAN compiler may find many other uses.
3.
Lack of a slick interface (the DOS version; the Windows version may be dierent). Programs that are point and click are nice UNTIL you want to do something even slightly
dierent from what the program's authors had in mind. Then your hands are tied ...
but not with ADAPT II.
Paul (Sisyphus) B. Laub

Dept. of Medical Oncology, Fox Chase Cancer Center, PA 19111 USA
On 6 Dec 1996 at 11:40:25
We use SCIENTIST a lot and are very happy with it. It is easy to use and has nice graphics.
Prof. Dr. Hartmut Derendorf
University of Florida, 100494, College of Pharmacy, Gainesville, FL 32610
146
On 8 Dec 1996 at 18:30:32
LaurentAs I have said in response to two recent queries like yours, you owe it to yourself to check
out SAAM II.
I've been in the kinetics business for almost 30 years and I'm now doing all my work in
SAAM II. It's got a neat graphical user interface, runs under Win95, WinNT, or MacOS,
has a bunch of hot-shot integration and parameter estimation algorithms, and it's not very
expensive. I've used the software to teach kinetics to more than 100 people in the last
three years, and they have been unanimous in their praise for how easy it is to learn.
Robert D Phair PhD: rphair.aaa.ix.netcom.com
On 8 Dec 1996 at 18:31:50

All the programs you mentioned are a variation on the theme of curve fitting. The
short coming as I see it (and I hope others might share their own viewpoints on this)
is that programs such as these give good equations and curve fits but provide little
in the way of useful PK parameters. Typically they give little more than the AUC,
half-life and lag-time. On the other hand, when one surveys, for example, Drug Metabolism and Disposition, the vast majority of papers dealing with pharmacokinetics provide tables which include these and other PK parameters (such as the Vd, Cl, MRT,
AUMC, etc.) as their primary results. Typically, these results are all based on noncompartmental assumptions.
I have to disagree with your conclusion as a general shortcoming about 'curve fitting' programs. Any general non-linear regression program that allows the user to define the model
will also allow any parameterisation the user wants. There is nothing to stop you parameterising a model in terms of Vd and CL (as opposed to elimination rate constants [like alpha and beta] and 'intercepts' [like A and B]. Unfortunately I suspect many of the programs you mention were not developed or maintained by pharmacokineticists and so they
oer a general 'mathematical' parameterisation without understanding the nature of the
application of PK models as a tool to understand biology.
AUC and AUMC have no intrinsic merit as PK parameters. They are simply intermediate
values which are usually obtained via non-compartmental methods and then applied to obtain the PK parameters of real interest i.e. CL and Vss.
147
I would say that most PK analysts today have moved away from the old A, alpha, B, beta,
and the K1O, K12, K21, V parameterisations of the two compartment model and now favour parameters that are more closely related to structure and function i.e CL, Vss, CLic
(inter-compartmental clearance) and V (central cpt volume).
Nick Holford
148
S EC T I O N 30
Pulse dosing of aminoglycosides

On 8 May 1996 at 10:40:53
Concerning the current trends in the dosing of aminoglycoside antibiotics (AGAs) consider the following:
1.
Pulse dosing of AGAs means high doses (5-7 mg/Kg) with long dosing intervals (usually
once every 24 to 48 hrs, depending the drug's half-life).
2. After a peak of 10 - 20 mg/L, the serum AGA level should ideally drop to undetectable
(<0.3 mg/L) several hours before the next dose is due.
3.
The higher peaks should enhance the antimicrobial ecacy; AGAs have
concentration-dependent kill rate. Although there are no controlled clinical studies
that show higher therapeutic ecacy with pulse dosing compared to the traditional
multiple daily dosing regimen, the available data indicate that pulse dosing is at least
as eective as the traditional method.
4. Pulse dosing may be safer; lower nephrotoxicity was demonstrated in at least one clinical study (Prins et al. Lancet 1993; 341: 335-339). Our own experience at the University
of Rochester Medical Center tends to support the same conclusion.
5.
AGAs have the so-called post-antibiotic eect (PAE) (continued suppression of bacterial growth even after the drug level has fallen below the MIC). The duration of the
PAE depends on the organism and on the preceding peak (within limits, higher peaks
give longer PAEs).
6. In general, for antimicrobial agents that have concentration dependent bactericidal action and a PAE, higher single doses with longer intervals are preferred.
7. For more information please e-mail me at nanaizi.-at-.frontiernet.net
You will find many references in the following:
1.
149
Am J Hosp Pharm 1994; 51:2016-2021
2. Pharmacotherapy 1995; 15:297-316

Dr. Anaizi, PhD RPh
Associate Prof of Pharmacology and Physiology, Univ. of Rochester (NY)
On 12 May 1996 at 14:10:09
We are currently dosing aminoglycosides qd per protocol which is an amalgamation of Gilbert's method and Quintalani's.
We routinely measure levels 12h after the first dose. This occasionally yields useful information. Just this week we had a 15 yo patient with severe abdominal trauma and liver injuries. The 12h level was unexpectedly elevated. We were able to modify the dose prior to
seeing an increase in SCr.
Does anyone have information in qd dosing in pediatrics? We are hesitant to use it in
younger chiledren and infants.
Carl Heisel
150
S EC T I O N 31
References on WWW
On 31 May 1996 at 10:59:41
To PK/PD Discussion group. I would be grateful for any information relating to the approved way of referring to articles or references taken from the www.
Janet Mifsud
Department of Pharmacy, Univeristy of Malta
On 3 Jun 1996 at 11:56:08
I doubt that there is a standard, formally approved format for citing material published on
the net. Most of the valuable material on the net has already been either published in the
"paper media" or present in scientific meetings. The important point is that we give due
credit by citing the original source; the exact format is of secondary importance. I would
be surprised if a formal format actually exists.
N. Anaizi
On 3 Jun 1996 at 11:56:12
On a separate note, is it *acceptable* to cite from the WWW knowing what an uncontrolled place it is (certainly judging by some WWW sites.)
Paul Baker
Pharmacy, Heartlands Hospital, Birmingham, UK
On 4 Jun 1996 at 11:44:17
However, every piece of information passed on should reference where it was obtained
and the source.
151
Remember there is no check of accuracy or credibility on any information posted via electronic means. Anyone with access may post data and we are dependent on the individual
for accuracy and viability. Many items are strictly the opinions of the sender not necessarily fact.
In short, beware of anything obtained unless it can be verified or checked for accuracy.
Joe Bishop
On 4 Jun 1996 at 11:44:18

On a separate note, is it *acceptable* to cite from the WWW knowing what an uncontrolled place it is (certainly judging by some WWW sites.)
Paul Baker
I wholeheartedly agree with Paul here. I recall seeing a recent report (from a poster submitted at an ASHP meeting I believe) that made the observation that up to 40% of the
postings on sci.med.pharmacy were "bad information." I would feel much more comfortable using peer reviewed material to prove a point (especially if it had to be good enough
to survive in court). If one did use material on the Web for a report you would probably
want to annotate the reference as to whether it was peer reviewed or not.
Richard Molitor, R.Ph.
Editor, "Molitor Monitor"
On 5 Jun 1996 at 11:05:49

On a separate note, is it *acceptable* to cite from the WWW knowing what an uncontrolled place it is (certainly judging by some WWW sites.)?
From the perspective of the journal 'Clinical Pharmacokinetics' I would be prepared to accept citations to WWW pages as a source of further information. There is no requirement for any citation in a paper that it must be a peer reviewed paper journal.
Nick Holford
Consulting Editor Clinical Pharmacokinetics
152
On 29 Dec 2012
Two comments (in 2012).

1.
Check references on the WWW and in this archive collection.
2. One method of citing WWW pages might be to list the URL, date accessed and
maybe the page title and source description. It could be useful to keep a pdf file or
printed copy of the page cited for your reference.
153
S EC T I O N 32
Sigmoid Emax and the logistic CDF

On 18 Mar 1996 at 09:50:24
I wish to get a better understanding of the development and relationship of sigmoid emax
modeling of quantal responses to the standard form logistic CDF. Can anyone suggest a paper in a statistics journal?
Nathan Pace, M.D.
On 19 Mar 1996 at 09:32:08
For quantal responses, logistic regression (using generalized linear models) clearly has theoretical advantage. The standard reference on generalized linear models is McCullagh, P.
and Nelder, J.A., Generalized linear models, 2nd ed., Chapman & Hall, New York,
1989.
I heard that some people may find it dicult to read, but I do not know
of anything easier.
Chuanpu Hu
On 22 Mar 1996 at 11:32:44
I have perused McCullagh and Nelder, Analysis of Quantal Response Data by BJT
Morgan (Chapman & Hall, New York, 1992), and Continuous Univariate Distributions, Vol 2, 2nd edition by Johnson, Kotz, & Balakrishnan (John Wiley & Sons, New York
1995) and can find no mention of sigmoid emax models or any related CDFs.
In the new monograph Nonlinear Models for Repeated Measurement Data by
Davidian & Giltinan (Chapman & Hall, New York, 1995) it is mentioned on page 241 in a
chapter about PK and PD analysis: "Derivation of a suitable PD model: unlike PK
154
modeling, this is usually done in a somewhat empirical fashion. By far the most commonly
used model is the so-called 'Emax' model, or some variation thereof..."
In my specialty (Anesthesiology) most PD papers report use of sigmoid emax models.
With the extensive developments in logistic regression, why do PD researchers continue
to use the sigmoid emax model - a technique which appears to not have the same rigorous
theoretical foundation as logistic models?
Nathan Pace
University of Utah
On 25 Mar 1996 at 09:44:46

With the extensive developments in logistic regression, why do PD researchers continue
to use the sigmoid emax model - a technique which appears to not have the same rigorous theoretical foundation as logistic models?
For the usual purposes of pharmacodynamic models the logistic function and the sigmoid
emax model are simply dierent parameterisations of the same model. IMHO the parameterisation of the sigmoid emax model (esp. EC50) is more helpful in understanding what is
being described. I understand logistic regression to mean the use of the logistic function
aka the sigmoid emax model to predict the probabilility of an event what e.g. as a function
of conc or dose. There is no reason to prefer the sigmoid emax model over the logistic
function because they are the same. Logistic regression is statistical shorthand for a particular applicaton of these models.
Nick Holford
155
On 25 Mar 1996 at 09:44:52
There may be theoretical advantages of logistic function over a sigmoid Emax model, however, from the practical point of view no significant dierence can be seen, since, after elementary transformations the sigmoid Emax equation
E=Emax.C**n/(C50**n+C**n)
is converted into:
ln(E/(Emax-E))=n.ln(C) - n.ln(C50)
156
S EC T I O N 33
Software for Tracking Clinical Pharmacy

Services
On 4 Dec 1996 at 10:42:47
Does anyone have the name of a good software package that we could use in our clinical
service to track interventions, kinetic consults, and their subsequent impact on dollars
saved or cost avoided? We are being asked to give hard data to support our existence. We
do regular kinetic consults and bill them as we would a drug. I would like something that
would be separate from the patient bill to track clinical activities.
I realize that much of our work results in cost avoidance but there is a substantial amount
that results in actual savings. We have all of these computers, now we need to put them to
work.
Robert G. Aucoin RPh
Peds Clinical Pharmacist. The Children's Center, Our Lady of the Lake RMC. Baton
Rouge, LA
On 5 Dec 1996 at 10:50:13
It is my impression that the Capcil program from Simkin in Gainesville, Florida provides
this capacity
John E. Murphy, Pharm.D., Professor and Head, Department of Pharmacy Practice and
Science
157
S EC T I O N 34
Theophylline clearance
On 5 Feb 1996 at 11:00:17
I am seeking information concerning theophylline clearance (population kinetics). I am

building a kinetic module for use at the hospital I work. Any information would be
greatly appreciated.
Doug Kidder R.Ph.
On 6 Feb 1996 at 12:55:45
There are several factors that can influence the calculation of a patients theophylline clearance in clinical practice. Drug interactions can have abrupt (ie cimetidine after 24 hours)
or delayed (e-mycin, starting or stopping tobacco) onset. Factors such as liver disease or
heart failure depend on the severity and presence of symptoms. This can some times
change on a daily basis. If the patient received a flu vaccination or has been recently under
or over compliant (Some patients will double up prior to arriving to the ER to avoid being
tubed). Severe COPD/Asthma requiring ventilation may depend on the presence of PEEP
>10mmhg (or presence of autoPEEP)(decreased cardiac output secondary to depressed venous return) or changes in ABG's. Infusion rates (was the rate equivalent to the total
amount givin in the past 24 hours) due to incompatibilities or administration error. Time
of level draw and the method used, especially if not at steady-state, to calculate the clearance can also influence your predictions (ie Koup vs Chu vs PK Bayesian software).
I hope this gives you a starting point and some things to consider
William Dager, Pharm.D.,FCSHP
158
On 7 Feb 1996 at 11:28:25
Due to the many factors which aect theophylline clearance, it is very dicult to develop
a population model which can include all cofactors and accurate predict the eect of each
cofactor on theophylline clearance. The best method is to just measure a serum
concentration. However, numerous articles are published on the eect of various factors
on theophylline clearance. They are:
Jusko WJ, et al. 1979 Factors aecting theophylline clearances: Age, tobacco, marijuana,
cirrhosis, congestive heart failure, obesity, oral contraceptives, benzodiazepine, barbiturates, and ethanol. J Pharm Sci, 68 (11), 1358-66.
This article is widely quoted and used in development of several already available
pharmacokinetic dosing software programs.
Reigelman S., et al. 1980 Factors aecting the pharmacokinetics of theophylline. Eur J
Respir Dis., 61 (Suppl 109), 67-82.
Richer M, et al. Hypoxia, arterial pH and theophylline disposition. 1993 Clin Pharmacokinet., 25, 283-99.
How well do these models work?
Casner PR, et al. A randomized controlled trial of computerized pharmacokinetics theophylline dosing versus empiric physician dosing. 1993 Clin Pharmacol Ther., 53, 684-90.
My experience with a similar unpublished study was the same; a population kinetic model
combined with dosage individualization based on serum concentrations does not improve
outcome of patients receiving theophylline as measured by length of hospitalization and
toxicity.
There are numerous studies in the literature on population theophylline pharmacokinetics, primarily in the late 1970's and 1980's. Good luck!!
Michael Burton
159
On 7 Feb 1996
It seems to me that any estimate of renal function without age in the equation would discount the fairly well established eect of age on renal function. You might wish to focus
on studies that have measured creatinine clearance and a drugs clearance and separated
out the age factor in that manner. That is, is there any dierence in clearance of a drug in
a 20 year old and an 80 year old who both have measured creatinine clearance of 90 ml/
min? I know there are such studies but don't have them readily available.
John E. Murphy, Pharm.D., Professor and Head, Department of Pharmacy Practice and
Science
On 8 Feb 1996 at 12:26:11
We have experience with a population based Bayesian forecasting model that does a pretty
good job taking in to account the various factors that alter theophylline clearance. The advantage of using this type of model is that it utilizes available serum concentrations as well
as population data. In the absence of serum concentration data, it gives a very good first
estimate of the likely clearance value.
Applied Pharmacokinetics, (Evans, Schentag, and Jusko, eds.) has a very complete
compilation of theophylline pharmacokinetic values in various populations. The tables are
all completely referenced so you can review the original literature and make up your own
mind. The discussion of various parameters in the text is also interesting.
Art Harralson
Professor and Vice-Chairman, University of the Pacific, School of Pharmacy
On 23 Feb 1996 at 10:59:52
Dear Doug,
From the sound of your question, the responses you've gotten our pretty abstract. I, too,
am a pharmacist in a hospital which routinely screens all patients on theo for estimated
levels and confirm them via actual levels. We use very simple equations to determine estimates because like most hospitals we have a lot of patients. This simple straight forward
estimate may be used if you like:
160
1.
Estimate Clearance in L/hr by: using Ideal Body Wt x .05 x disease states
Here you'd factor in specific disease adjustments

Examples: asthma = 1.0 smokers use 1.4 see applied therapeutics for a complete list of factors associated w/variation in theophylline elimination.
2. Next calculate Vd using ABW * 0.5
3.
Knowing the relationship b/w VD and cl we can determine t 1/2 = vd/cl * 0.693 (usu
8hrs)
4. Estimate Cpss using: Cpss = (dose/24hr) divided by CL = mg/l

Hope this is what your after. It's fairly accurate and quick. Applied therapeutics also discusses expected changes in levels when certain drugs which interfere w/clearance are
added.
Anna
161
S EC T I O N 35
Tissue Homogenizers
On 22 Mar 1996 at 11:32:46
I am interested in hearing about your experiences with tissue homogenizers - especially

the pros and cons of Potter-Elvehjem (teflon coated rods?) versus the handheld electric "tissue grinders". The goal is to prepare liver microsomes.
J. Vora
Butler University, Indianapolis, IN, USA
On 25 Mar 1996 at 09:44:48
It has been my experience that the PE tissue homogenizers work very well for liver. Liver
tends to be a soft tissue ang grinds easily. Other tissues, for example gut tissues, tend to
get wrapped up in the grinder and may jam it, thus breaking the homogenizer ( and they
are expensive to replace). The problem that we have encountered with the electric homogenizers for microsomal work is that they tend to generate a lot of heat and may inactivate microsomes. Even the PE tends to generate some heat, and we place the grinder in an
ice bath while we grind. The other problem with the electric homogenizers is that it is
sometimes dicult to get all the tissue back out of them without excessive rinsing. It is
easier to rinse the PE homogenizer. Hope that wasn't to graphic for anyone !!
Brian Corrigan
162
S EC T I O N 36
Toxicokinetic Data and LOQs

On 19 Dec 1996 at 10:59:58
I have recently been asked to analyze some toxicokinetic data (involving the pooling of
data from a number of animals to generate a series of mean conc v. time values, which are
then subsequently analyzed in a non-compartmental fashion) and have been faced with
triplicate determinations of which one or even two of the triplicates are below the LOQ
for the assay, without being "not-detected" per se. It has been suggested to me that, rather
than leaving the mean value for these points undetermined (thereby losing that point from
the graph altogether, and analysing the remaining points only) I instead assign a value of
half the LOQ to these determinations, and thus derive a mean for inclusion in the graph
and analysis. I am instinctively uneasy about this, but in the context of TK analysis, where
sampling is very limited, it would be of enormous benefit to be able to ascribe a value to all
the time points available.
Does anyone have any comments on this approach?
Ray French.
On 20 Dec 1996 at 14:02:55
It depends on what the LOQ of the assay is? Personally I prefer to use that one particular
concentration for which you have a value rather than guessing for the samples with LOQ.
Other words use one value that have a real number and don't use take the value two LOQ
samples LOQ = ? of the lower limit of quantitation (assuming two out of three determinations are LOQ).
Prasad Tata, Ph.D.
Otsuka America Pharmaceuticals, Inc.
On 20 Dec 1996 at 14:03:09

163
Certainly these points provide some information, an approximate upper-bound if nothing

else. Some statistical software will allow their use as constraints. If you choose to assign a
specific value, recognize that the statistical weighting given this value must reflect the uncertainty.
Richard Scheyer, M.D.
Dept. Neurology, Yale School of Med., P.O. Box 208018, New Haven, CT 06520-8018 USA
On 20 Dec 1996 at 14:03:24
In similar situations with clinical PK studies, I have ascribed zero to those values.
Lester Gibbs
Penederm, Inc., Foster City, CA
On 20 Dec 1996 at 14:04:20
An old problem. Our arbitrary solution is if at least one data point in the set is above the
LOD, we use the LOD for the remaining points. If the data falls between the LOD and
the LOQ we use the data. In either case it must be clear that these points are estimates.
Ed Garner
164
S EC T I O N 37
Vancomycin Clearance from Dialysis

Membranes
On 9 Jul 1996 at 09:29:33
I read an article recently about some newer membranes used in dialysis removing vanco to
a higher degree than what older dialysis equipment did. I can't seem to locate where I
read this article. Does anyone else recall recently reading of this and if so could you give
the the reference info?
Randy
On 10 Jul 1996 at 11:17:21
Matzke GR 1994 Pharmacotherapeutic consequences of recent advances in hemodialysis

therapy. 1994 Annals of Pharmacotherapy 28, 512-14. contains a reference of this type.
Joan Korth-Bradley
On 11 Jul 1996 at 09:36:08
Here are some useful references I have on the topic:

Bastani B, Spyker DA, Minocha A, Cummings R, Westervelt FB 1988 In vivo comparison
of three dierent hemodialysis membranes for vancomycin clearance: cuprophan, cellulose
acetate and polyacrylonitrile. Dialysis Transplantation, 17, 527-543
Lanese DM, Alfrey PS, Molitoris BA 1989 Markedly increased clearance of vancomycin
during hemodialysis using polysulfone dialyzers. Kidney Int, 35, 1409-1412
Torras J, Cao C, Rivas MC, Cano M, Fernandez E. Montuliu J 1991 Pharmacokinetics of
vancomycin in patients undergoing hemodialysis with polyacrylonitrile. Clin Nephrol, 36,
35-41
DeSoi CA, Sahm DF, Umans JG 1992 Vancomycin in elimination during high-flux hemodiaylsis; kinetic model and comparison of four membranes. Am J Kidney Dis 20, 354-360
165
Barth RH, DeVincenzo N, Zara AC, Berlyne GM 1990 Vancomycin pharmacokinetics in

high-flux hemodialysis. J Am Soc Nephrol, 1(4), 387. Abstract
Schoumacher R, Chevalier RL, Gomez RA, Rogol AD, Cummings R, Spyker DA 1989 Enhanced clearance of vancomycin by hemodialysis in a child. Pediatr Nephrol, 3, 83-85
Quale JM, O'Halloran JJ, DeVincenzo N, Barth RH 1992 Removal of vancomycin by highflux hemodialysis membranes. Antimicrob Agents Chemother, 36, 1424-1426
Pollard TA, Lampasona V, Akkerman S, et al 1994 Vancomycin redistribution: dosing recommendations following high-flux hemodialysis. Kidney Int, 45, 232-237
Touchette MA, Patel RV, Anandan JV, Dumler F, Zarowitz BJ 1995 Vancomycin removal
by high-flux polysulfone hemodialysis membranes in critically ill patients with end-stage
renal disease. Am J Kidney Dis, 26, 469-474
Bohler J, Reetze-Bonorden P, Keller E, Kramer A, Schollmeyer PJ 1992 Rebound of plasma
vancomycin levels after haemodialysis with highly permeable membranes. Eur J Clin Pharmacol, 42, 635-640
Welage LS, Mason NA, Homan EJ 1995 Influence of cellulose triacetate hemodialyzers
on vancomycin pharmacokinetics. J Am Soc Nephrol, 6, 1284-1290
Reggie Frye
On 11 Jul 1996 at 09:36:10
See June 1, 1996 AJHP, p 1339, Letter: More information on vancomycin clearance by new
hemodialysis membranes.
Bill Budris
166
S EC T I O N 38
Vancomycin Question
On 3 Dec 1996 at 14:18:33
1.
Regarding vanco kinetics, our instructor gives the following equation:
Kel = 0.0044 + 0.00083(CrCl)

I can't find this in any of my kinetics resources, and it gives a very dierent answer from
the more commonly used Kel = ln(Cp1/Cp2)/time. So my question is, is this a valid equation, and if so, is CrCl expressed in ml/min?
2. Is it necessary to wait 1.5 half-lives before drawing the first vanco blood level?
3.
If your vanco infusion is given over 2 hours instead of 1 hour, do you still need to wait a
full 3 hours to account for the distribution phase before drawing a peak?
Thanks again in advance. I hope everyone had a most excellent Thanksgiving.

Catherine Heyneman, Pharm.D.
ISU College of Pharmacy, Pocatello, ID 83209
On 4 Dec 1996 at 09:59:05

1.
Regarding vanco kinetics, our instructor gives the following equation:
Kel = 0.0044 + 0.00083(CrCl)

I can't find this in any of my kinetics resources, and it gives a very different answer from the more commonly used Kel = ln(Cp1/Cp2)/time. So my question is, is this a
valid equation, and if so, is CrCl expressed in ml/min?
I expect CrCl is in ml/min here, i.e., a CrCl of 100 ml/min would yield Ke of 0.0874,
which probably gives you a half-life of about 8 hr.
2.
Is it necessary to wait 1.5 half-lives before drawing the first vanco blood level?
Define "first level"- first level after a loading dose? If so, probably not (see
later).
167
3. If your vanco infusion is given over 2 hours instead of 1 hour, do you still need
to wait a full 3 hours to account for the distribution phase before drawing a peak?
Why draw a peak any way? Vanco peaks have no real impact on outcome, and are dicult
to interpret due to the issues you are pointing out here. I'd suggest either monitoring concentrations using troughs only (goal: 10-13 mg/L) or using a midpoint concentration (goal:
15-19 mg/L) to estimate AUC and hence daily dose.
Steve Ebert
On 4 Dec 1996 at 10:41:40
1. The equation Kel=0.0044 + 0.00083(ClCr) is derived from work done in the late 70's
and early 80's by Mollering using Bayesian modeling form POPULATION kinetics of
Healthy adults. Therefore, clinicians must evaluate the patient in question prior to envoking a particular nomogram or equation to a specific patient. An equation I use in clinical
practice to estimate the inital patient elimination rate constant is, CL= (Vd) (Kel). This
equation is more patient specific in that one integrates the patient specific serum creatinine to calculate Cl. Many argements can be posed such as aminoglycoside as well as glycopeptides clearence is not 100% proportionate to creatinine clearence; however, the equation is more individualized to the patient in question and allows for error on conservative
if clearence is high (note if serum creatinine is < 1 mg% use 1 ) something the other equation does not do.
2. Vancomycin has been shown to distribute via more than one compartment model ( Applied Phamracokinetics, 1992) and precise time for distribution has not been clearly established; however, this poses no problem clinically because definitive vancomycin peak levels
have not been established and toxici ty associated with 2hour post infusion (initiation) levels < 60mg/l have not b een substantiated. The longer you wait the better, as the sole purpose of drawing levels is to obtain patient specific pharmacokinetic parameters so you can
attain desired levels. 3. One should wait at least 1hour after adminstration to allow for distribution of any givnen dose reguardless of infusoin time. Patients with rapid clearence are
will eliminate the drug if "peak" (because it really is not a peak) is drawn too soon.
I hope this is helpfull to you and hope look forward to your evaluation of the information!
Ruben Atencio R.Ph., B.C.N.S.P.
168
On 4 Dec 1996 at 10:42:15
1. Reference is Matzke GR, et al. 1984 Pharmacokinetics of vancomycin in patients with

various degrees of renal function. Antimicrobial Agents and Chemotherapy, 25, 433-7
Creatinine clearance is expressed as ml/min.
There are many reasons why a population prediction of k (and t1/2) may not match calculations from actual patient values.
* Population predictors such as these are based on regression of k vs CLcr in a number of
patients. The are value is often not too high.
* Vancomycin concentration measurements often a problem if drawn early after an infusion
* etc, etc, etc - see standard texts for such explanations
The equation is probably as "valid" as any other similar type predictor taken from a sample of patients that may or may not be reflective of the patient you are treating.
P.S. Population predictors for a number of drugs can be found in my book (cheap advertising, eh) Murphy JE (ed). Clinical Pharmacokinetics Pocket Reference. American Society of Health-System Pharmacists, Inc., Bethesda, MD, 1993.
2. The usual recommendation is one to two HOURS (I assume this is what you meant)
after a one hour infusion in order to avoid distribution phase when using onecompartment model approaches to analysis. P.S., the equation above is for onecompartment approaches.
3. The longer infusion time will mask more of the distribution phase. However, many still
recommend waiting the hour. As long as you aren't using a short interval waiting the extra
time should not be a problem and may be a benefit in insuring the infusion is actually completed.
169
On 5 Dec 1996 at 10:28:35

Why draw a peak any way? Vanco peaks have no real impact on outcome, and are difficult to interpret due to the issues you are pointing out here. I'd suggest either
monitoring concentrations using troughs only (goal: 10-13 mg/L) or using a midpoint
concentration (goal: 15-19 mg/L) to estimate AUC and hence daily dose.
I generally agree with the above but have a minor philosophical quibble. IMHO the point
of measuring one or more concs is to estimate clearance so that the maintenance dose rate
can be individualised to achieve a specific target conc. A single conc cannot estimate an
AUC. It can estimate clearance (and you can derive AUC if you wish but that is unnecessary because MDR comes directly from Clearance and Target Conc). If you have several
concs then you can calculate an AUC and use that to estimate clearance.
Measuring two concs e.g. 'peak' and 'trough' allows a more precise estimate of PK parameters. The point of measuring the concs is to estimate clearance NOT because the MEASURED concs at particular times are themselves are related to outcome.
Outcome should to be related to the target conc. For almost all drugs the target conc is
still something of a guess but outcome for vanco may be related more closely to average
steady state conc [or AUC if you wish - they are equivalent] and thus Clearance is the parameter you need to estimate to individualise dose.
If you only measure one conc then a mid-dosing interval conc will be closer to the average
conc and thus more readily related to clearance. A trough conc implicitly relies more on assumptions about volume of distribution than the mid-point conc.
Nick Holford
On 5 Dec 1996 at 10:32:13

The first equation relates vancomycin elimination rate (in 1/h) to >creatinine clearance in ml/min, and originates from Figure 2 of a paper by Matzke and coworkers(Matzke
et al 1984).
We have successfully utilized this equation in a pharmacy based program designed to individualize initial doses of vancomycin for patients at the Bualo General Hospital.
170
The second equation requires administration of the drug and the acquisition of appropriately timed plasma concentrations. However, this approach has the obvious advantage of
allowing the direct estimation of the elimination of vanco (or any other drug) in the
patient. We also make use of this equation to aid in the adjustment of vanco doses to
achieve desired plasma concentrations (i.e., follow-up).
The relationship of vancomycin concentrations to therapeutic eects and the pharmacoeconomic benefits and of vancomycin therapeutic drug monitoring have been questioned
in the literature (Cantu et al 1994; Pryka et al 1991). However, two papers have been published which suggest that PK-based dosing has pharmaco-economic benefits. The first paper, by Lake and Peterson in 1988, claims that PK-based initiation of vanco therapy may
lead to dramatic reductions in drug acquisition costs (Lake & Peterson 1988) (this has been
our experience at BGH). The second paper, which has just been published, indicates that
vancomycin TDM may reduce overall therapy costs by decreasing the incidence of vancomycin nephrotoxicity (Fernandez de Gatta et al 1996).
At BGH, we obtain peak vancomycin concentrations 1 hour after the end of a 1 or 2 hour
infusion of vanco (we use 2 hour infusions for patients receiving doses greater than 1g or
for patients who develop red neck syndrome).
Joseph Balthasar, Ph.D., Rph
Clinical Assistant Professor, SUNY at Bualo, Department of Pharmaceutics
Cited papers:
Cantu, T. G., Yamanaka-Yuen, N. A., Lietman, P. S. 1994 Serum vancomycin concentrations: reappraisal of their clinical value. [Review]. Clinical Infectious Diseases 18, 533-43
Hernandez de Gatta, M. M., Calvo, M. V., Hernandez, J. M., Caballero, D., San Miguel, J.
H., Dominguez-Gil, A. 1996 Cost-eectiveness analysis of serum vancomycin
concentration monitoring in patients with hematologic malignancies. Clinical Pharmacology
Therapeutics, 60, 332-340
Lake, K. D., Peterson, C. D. 1988 Evaluation of a method for initiating vancomycin therapy: experience in 205 patients. Pharmacotherapy, 8, 284-6
171
Matzke, G. R., McGory, R. W., Halstenson, C. E., Keane, W. F. 1984 Pharmacokinetics of

vancomycin in patients with various degrees of renal function. Antimicrobial Agents Chemotherapy, 25, 433-7
Pryka, R. D., Rodvold, K. A., Erdman, S. M. 1991 An updated comparison of drug dosing
methods. Part IV: Vancomycin. [Review]. Clinical Pharmacokinetics, 20, 463-76
On 6 Dec 1996 at 10:34:57
I have always thought that a peak taken after the distribution phase and in the elimination
phase (i.e. at least 2 h post vanco infusion) could be used with a trough to get a fairly dood
idea of T1/2 elim.
Dr Les White
Department of Microbiology, Southmead Health Services NHS Trust
Bristol BS10 5NB, UK.
http://www.ibmpcug.co.uk/~lwhite/index.html
On 6 Dec 1996 at 10:35:31
Nick, I think we're in agreement. We obtain a single concentration midway in the doing
interval because 1) it provides some estimate of Cl; and 2) it's the most cost-eective way
to obtain some useful information. Obviously more concentration points will allow for
better estimates of AUC/Cl, but I doubt this helps clinically.
Steve Ebert
On 8 Dec 1996 at 18:32:19

I have always thought that a peak taken after the distribution phase and in the elimination phase (i.e. at least 2 h post vanco infusion) could be used with a trough to
get a fairly dood idea of T1/2 elim.
That is correct. And with a little bit of extra work you can estimate what you really need
to know to adjust dosing i.e. the clearance.
Nick Holford
172
173
4
1997
174
S EC T I O N 1
Adjusted weight-based dosing for LMWHs

On 23 Jun 1997 at 12:04:11
I have a therapeutic dilemma for which I can find no good information.

Our hospital has begun using dalteparin both for DVT prophylaxis following orthopod
surgery and for the initial treatment of an existing DVT. We have recently added enoxeparin to trial for DVT prophylaxis following knee prosthesis surgery.
I am concerned about using a straightforward 100 U/kg (for dalteparin) bid schedule for
treatment of established DVT. In an obese patient (and this has recently been a real case)
weight-based dosing results in a calculated dose that seems very high to me. My concern
involves the volume of distribution of this drug. My thinking is that an obese patient
would not have a proportionately higher volume of distribution but a dose calculated
strictly by kilogram of real body weight would result in a huge dose (in the case at hand
15000 units bid).
I cannot find *any* good info on the partition/distribution of dalteparin or any other
LMWH.
If someone is heavy and well-muscled then I would expect a proportionately greater vascular volume, which is the volume these agents appear to distribute to. However, if someone's greater weight is due to lipid tissue, then I would not, and a straightforward unit/kg
dose would, I'm afraid, result in dangerous over-coagulation.
I haven't gotten very useful info from the manufacturer, just that the Vd is between 40-60
mL/kg. The range for Vd that I've found in the literature for dalteparin is 3-11 L.
Bottom line--should dalteparin (and other LMWHs) be dosed based on ideal/lean body
mass?
175
On 25 Jun 1997 at 10:29:39
We have just performed a study at our hospital looking at the pharmacokinetics of dalteparin in obese and normal weight individuals. The study was undertaken by one of our pharmacists (Julie Yee) in conjunction with myself. We are about to submit for publication, but
here are a few interim findings.
I have a therapeutic dilemma for which I can find no good information.
So did we...
I am concerned about using a straightforward 100 U/kg (for dalteparin) bid schedule
for treatment of established DVT. In an obese patient (and this has recently been a
real case) weight-based dosing results in a calculated dose that seems very high to
me. My concern involves the volume of distribution of this drug. My thinking is that
an obese patient would not have a proportionately higher volume of distribution but a
dose calculated strictly by kilogram of real body weight would result in a huge dose
(in the case at hand 15000 units bid).
Our recommendations for dosing dalteparin, prior to our study, appear similar to yours
(200 iu/kg sc once daily [DVT] or 120 iu/kg sc bid [massive DVT or PE]). Given this an average patient, 70kg, would receive either 14000 iu or 16800 iu daily.
I cannot find *any* good info on the partition/distribution of dalteparin or any other
LMWH.
Neither could we.

I haven't gotten very useful info from the manufacturer, just that the Vd is between
40-60 mL/kg. The range for Vd that I've found in the literature for dalteparin is 311 L.
This is about what we found in the literature.

Bottom line--should dalteparin (and other LMWHs) be dosed based on ideal/lean body
mass?
The answer is not all that clear. To date we believe that the risk of bleeding seems to be
related to the peak concentration, and hence Vd would be important. Some obese patients
that we have treated with high doses (200 iu/kg/d) have had minor bleeding complications.
However the trough is also important to maintain clinical eect, and hence Cl is important. In our study Vd correlated poorly with lean body weight {as determined by: LBW
(kg) = (height (cm) - 150 cm)*0.9 + 45 kg [+ 5 kg(Male)]} with an r2 of 0.05. Vd correlated
better with weight adjusted body weight r2=0.56 and total body weight r2=0.52 (total body
weight ranged from 55 to 155 kg). (Weight adjusted body weight was determined as LBW +
40% of the dierence of total body weight and LBW.) Obviously given the moderate r2
not all obese patients had large Vds and therefore there is some risk of bleeding when
obese individuals are dosed based on their total body weight.
176
We currently recommend either:

1. Dose on total body weight up to a patient weight of 90 kg. Heavier patients are dosed
as if they weighed 90kg (maxm dose/day is therefore either 18000 iu or 21600 iu), or
2. Dose on weight adjusted body weight (this isn't popular with the house sta!).
Steve Duull
Dept of Clinical Pharmacology, Christchurch Hospital, Private Bag 4710, CHCH, New
Zealand
177
S EC T I O N 2
Adsorption of Lipophilic Drug to

Polycarbonate Membrane
On 19 Jun 1997 at 13:29:34
I have been evaluating drug absorption by using Caco-2 cell monolayer. In the case of
high lipophilic compound, I cannot often reject the influence of adsorption of drug to the
polycarbonate membrane which supports Caco-2 cell monolayer. So, accurate permeability coecient of the drug cannot be evaluated
I would appreciate if any members of PharmPK can advise me on what experimental conditions should be applied in order to avoid the drug adsorption.
Teruaki Okuda
On 23 Jun 1997 at 12:03:03
Excellent question, however, I do not have any clear answer at this point. I am also using
Caco-2 as a screen in drug discovery and have essentially experienced same problem of
adsorption/absorption of "grease balls" (a term used by Stella for highly lipophilic compounds) to In Vitro system (transwell and membrane). This problem severely limits the use
of existing In Vitro systems (both transwell and vertical diusion chamber system by Costar) as far as lipophilic compounds are concerned. In a two compartment system such as
these, doing an additional experiment with a blank set (one without Caco-2 monolayers)
also presents mathematical challenges as far as correction due to adsorption/absorption is
concerned.
Some other approaches such as the use of solvents to minimize this problem can aect the
integrity of the monolayers. The use of solvents for recovery form the receiver side at the
end of sampling (basal or serosal side) can be tried but the amount bound to the donor
side (apical of mucosal for forward transport) will still pose a problem. Again, donor samples can be taken at the beginning and at the end of experiments to calculate total recovery, but that still does not completely solve the problem.
178
I hope I have described the problem in detail and would appreciate more thoughts on this
matter.
Gopal Krishna
On 23 Jun 1997 at 12:12:45
This is a classic problem in cell physiology. One important class of experiments that could
help is characterization of the kinetics of drug adsorption to the polycarbonate membrane. A good place to start is to load the membrane (with no cells) with the drug for several fixed loading periods and several doses, then evaluate the eux kinetics by removing
the loading solution, washing quickly, and then sampling the eux medium as frequently
as practical thereafter. A kinetic model of the adsorption process can then be constructed
based on the loading and eux data. You can then fit the transport data with a model of
both the polycarbonate membrane and the cell monolayer. The major diculty you will
face is that the total binding capacity of the PC membrane may not be the same with and
without cells. Nevertheless, you should be able to place an upper bound on the influence
of adsorption. You will want to fit the data from cell experiments and the data from nocell experiments simultaneously. This is relatively straightforward with modern software
tools.
Alternatively, you may want to test other growth surfaces, but my experience is that adsorption is never negligible, and the best approach is to include the support membrane in
your PB-PK model. Analysis is always cheaper than more experiments. Indeed, this is one
of the principal motivations for moving to complex kinetic models.
Robert D. Phair, Ph.D.
http://webcom.com/rphair
179
S EC T I O N 3
Altered Pharmacokinetics by Solid Tumor

On 6 May 1997 at 11:53:11
We are evaluating alterations in pharmacokinetics of the anticancer drug when coadministered with chemo-sensitizers for overcoming P-glycoprotein mediated multi-drug
resistance in solid tumors. As controls, we are using normal (tumor-free), and MDR knockout mice. It is likely that the tumor itself can alter anticancer drug PK. If anybody in this
group has experience in this area (alteration of PK caused by tumors), their input into the
design of such experiments would be most welcome and looked forward to.
Regards,
Rajesh Krishna
BC Cancer Agency
On 12 May 1997 at 15:55:39
Dear Dr. Krishna:

We have been studying and documenting the eect of modulators on the PK of 5-FU in
solid tumors (especially breast and colon in humans), and in several rat.
Let me begin by referring you to a paper we presented in 1995 at the AACR meeting entitled: "Pharmacokinetic Guidance of Drug Modulation: Initial studies with 5-fluorouracil"
(#2141). We have a number of such studies, which we hope to publish shortly in full detail.
The main thrust of our approach is the use of noninvasive methods (NMR spectroscopy
and nuclear imaging) to monitor drug pharmacokinetics at their target sites, rather than
inferring what might happen based on blood data. The latter do not yield reliable information on the time course of drugs at their target sites, and we had shown (J. Pharm. Sci.
53:873-877, 1986) that inter-animal variations (and obviously, inter-patient variations) will
180
cover subtle changes unless the same individual can be used as his/her own control. Hence,
noninvasive methods are absolutely required.
|
On 12 May 1997 15:56:52 -0500

A few years ago I did some studies on etoposide in children with Cyclosporin A as a modifier of PGP, and found significant changes in clearance. I gather this is a fairly well described eect. I am unclear why you think tumors in mice might be altering drug PK
themselves, unless you are allowing them to reach enormous proportions.
Stephen Lowis
Department of Paediatric Oncology, Bristol Royal Hospital for Sick Children
On 13 May 1997 at 11:22:18
Stephen:
Thanks for your note. Yes, it is a well described eect that inhibitors or more appropriately, modulators of PGP alter significantly the anticancer drug PK, particularly clearance,
when co-administered for MDR reversal. However, it is possible that the tumor by itself
can alter the PK of the anticancer drug (healthy vs tumor bearing animals) by altering drug
metabolism. We are studying the eects of PSC 833 on doxorubicin PK and the possible
eects of PSC 833 on the metabolites of DOX in solid tumor bearing experimental animals (~100-200 mg tumors) - and would need to delineate the eects of the tumor itself (effects of the tumor vasculature, angiogenesis, microvascular environment on drug uptake
and disposition as well as to address the issue of metabolism in tumors).
Rajesh Krishna
181
S EC T I O N 4
Aminoglycoside Dosing in Critical Care

On 7 Nov 1997 at 11:27:50
I work in a multidisciplinary ICU and I was wondering if anyone has heard of software to
aid management of aminoglycoside dosing and dose interval in critically ill
patients...taking into account their level of renal dysfunction etc. We normally use a oncedaily dose regime adjusted according to trough levels. Also is anyone aware of specific data
on the pharmacokinetics of gentamicin in this patient population (ie sepsis etc)
Dr. A. Ferguson
On 11 Nov 1997 at 13:28:02
You may consider trying Adapt II or USC Pak software. The former will require more programing experience. There is a website of Adapt II (Biomedical Simulations Resource Univ of CA - LA). Information about USC Pak can be obtained from Roger Jellife. There
are other programs with less versatility such as the Abbott Program, but I have not used
this. If you plan to use a program for dosing - one capable of Bayesian estimation would
be best. With Bayesian estimation, obtain serum concentrations about 1.5 to 2.5 times the
expected half-life.
Trough levels are not the best for once daily dosing. If dosed correctly, the aminoglycoside
concentration should be not-detectable at the trough.
David Nix
On 18 Nov 1997 at 13:42:11
There are several software packages that are designed to be helpful in aminoglycoside dosing in critically ill patients. The Abbottbase one is good, and also the MW/Pharm software from Groningen, the Netherlands, and OPT, from Glasgow. Our own USC*PACK
software has been around for the longest of any software package I know, and is specifi182
cally designed to model the behavior of AG's and other drugs so that the pk model of the
drug can keep up with rapid changes in a patient's renal function from dose to dose, for example, and also with changing body weight from dose to dose. CCr can be computed from
a pair of serum creatinine samples and age, gender, height, and weight, so that serum creatinine can be changing widely from sample to sample, and the model can keep up with
these changes.
There are population AG models for general medical patients, ICU patients, otherwise
healthy young patients (teens and early 20's), those with spinal cord injuries, and newborns. You can also enter and store any other PK pop model for any drug you wish, as long
as it has an absorptive, a central, and (if needed) a peripheral compartment. Elimination
can be specifically expressed as an increment of Kel per unit of CCr, with a nonrenal intercept.
These PK models use Bayesian approaches to make individual, patient-specific PK models. These can also be linked to models of diusion into porous spherical objects such as
endocardial vegetations of a stated diameter, using diusion coecients obtained from animal studies, to compute possible drug concentrations in its various layers, and in the center of such a vegetation, and also to simulate the contribution of the post-antibiotic eect.
The PK and the diusion models can also be linked to models of bacterial growth and kill
which can be used to evaluate the ability of a certain regimen to kill well or not under defined circumstances. These Zhi models, developed with Drs. Pascal Maire and Xavier Barbaut, use data of the rate constant for growth in the logarithmic phase and the most rapid
kill rate found with in vitro studies. This can be combined with data of each patient's
known or estimated MIC to then model the possible growth and kill of organisms under
such defined circumstances, to better understand the ability of various regimens and serum concentration profiles to be eective or not.
Roger W. Jellie, M.D.
USC Lab of Applied Pharmacokinetics, CSC 134-B, 2250 Alcazar St, Los Angeles CA
90033
183
On 18 Nov 1997 at 13:44:17
In terms of software for dose individualization of Ags and indeed many other drugs there
are a number of programs available. A review by Bungton et al (Clin Pharmacokinet
1993; 25:205-216) specifically discusses this issue. In essence Bayesian methodology seems
to be widely used and appears to be very useful. To my knowledge all programs that use
Bayesian methods use the maximum *a posteriori* (MAP) objective function, originally described by Sheiner et al (Clin Pharmacol Ther 1979;26:294-305). Minimization of this objective function will locate the mode values of the parameters. Therefore any computer
program that uses the MAP objective function and uses an accepted method of minimization of this function, eg simplex, Marquardt Levenberg (etc) will essentially yield *identical* results. A good program will also allow you to input your own prior model for a new
or existing drug (which would be useful for your own patient group).
In summary therefore it shouldn't matter which software you choose that meet this criteria, and therefore choice should be based on cost, availability and backup service.
Also is anyone aware of specific data on the pharmacokinetics of gentamicin in this
patient population (ie sepsis etc)
There are some publications on this already. A useful initial reference is given by: Dager
(Ann Pharmacother 1994, 28, 944-951).
Steve Duull
Christchurch, New Zealand
184
S EC T I O N 5
Amiodarone Pharmacokinetics
On 1 Apr 1997 at 13:58:02
Hello, I am a Clinical Pharmacist from Greece and I would like to know more about
pharmacokinetics of amiodarone (about compartment modeling, equations etc.) Furthermore I would appreciate if you inform me about software or books about clinical pharmacokinetics of amiodarone.
Stavroula Theophanous
Clinical pharmacist
On 2 Apr 1997 at 13:16:23
There is a wealth of information on the PK of amiodarone. Paul Nolan (Pharmacotherapy

1997; 17 (2 Pt 2): 65S-75S recently reviewed the PK/PD of intravenous agents for ventricular arrhythmias that lists the most recent amiodarone PK papers.
Joan Korth-Bradley
Clin PK, Wyeth-Ayerst Research
185
S EC T I O N 6
ANOVA for Comparison of Bioavailability

On 11 Dec 1997 at 14:04:56
I think it is possible to use Anova for the purpose of comparison of AUC (after log transformation) and MRT and MAT as well. Could that be confirmed and does anyone knows a
textbook or an article which describes it?
Professor P. Maincent
Laboratoire de Pharmacie Galenique
On 18 Dec 1997 at 10:37:12
You can use ANOVA to compare everything. The major problem is that AUC itself as calculated by trapezoidal summation (a common approach in bioavailability/bioequivalence
studies) is a biased estimate of the true AUC. Since MRT and MAT include a higher moment, they are even more biased. Thus, any conclusion you get after applying ANOVA is
doubtful.
186
S EC T I O N 7
Antimicrobial Pharmacokinetics in the Eye

On 14 Apr 1997 at 12:28:24
I am an ophthalmologist and part of my teaching responsibilities is teaching residents the

pharmacokinetics, pharmacodynamics etc of antimicrobial agents (anti-bacterial, viral, fungal, etc.) as related to the eye (e.g. corneal, scleral penetration, etc.) including topical therapy, local injection, and systemic administration. Any and all help regarding a syllabus and
other teaching aids would be greatly appreciated. Thank you.
Martin Mayers, MD
Director, Department of Ophthalmology, Bronx Lebanon Hospital Center, Albert Einstein College of Medicine
On 15 Apr 1997 at 16:55:10
Any bibliography should include papers by Mike Barza, MD. You should also check the
textbook, Antibiotics in Laboratory Medicine, by Victor Lorian, ed.
Steve Ebert
On 15 Apr 1997 at 16:58:51
Although they do not address antimicrobials specifically, here some excellent extensive
general reviews of ocular pharmacokinetics:
In: Ophthalmic Drug Delivery Systems edited by Ashim K. Mitra
) Ch. 4. Ocular Pharmacokinetics/Pharmacodynamics (by Schoenwald)
) Ch. 8 Mathematical Models of Ocular Drug Transport and Disposition (by Himmelstein)
187
In: Pharmacology of the Eye edited by M.L. Sears (Handbook of Experimental Pharmacology Series vol. 69)
) Ch. 2 Ocular Pharmacokinetics (by Maurice and Mishima)
Paul Damian PhD, MPH
Program Coordinator, Western Region, Food Animal Residue Avoidance Databank, Dept.
of Environmental Toxicology, University of California, Davis, CA 95616
On 23 Apr 1997 at 11:07:06
Suggestions for course syllabus:

A. Drug tear film kinetics
1.
initial tear concentrations
2. drainage/spillage
3.
tear turnover
4. systemic absorption
B. Formulation eects
1.
viscosity
2. suspensions
3.
ointments/gels
4. ocuserts
5.
drug concentration
6. osmolarity
7. contact lenses
C. Corneal Penetration
1.
188
3 layers
D. Drug characteristics and ocular penetration

1.
molecular size
2. water solubility
3.
protein binding
4. susceptibility to active transport processes

E. Periocular admin
1.
Subconjunctival inj
2. Subtenons inj
3.
Retrobulbar inj
F. Intravitreal inj
Here are excellent articles you may find helpful:
Timothy S. Lesar and Richard G. Fiscella, 1985 Antimicrobial Drug Delivery to the Eye,
Drug Inte!igence and Clinical Pharmacy 19 642
Ronald D. Schoenwald 1990 Ocular Drug Delivery, Clin. Pharmacokinet, 18 (4), 255-269
I just finished a course section on ocular pharmacokinetics and have many more references. The most important factors I feel should be taught to future prescribers are:
1. the cornea saturates so while 1 drop is good, 2 drops is a waste of time and money for
some drugs eg. timolol
2. tear film kinetics: the eye can only hold 30 L transiently and the tear film takes up 10
L----a drop contains 50 L----do the math! Pretty expensive to have drug on the cheek.
3. practical dosing concerns: Write on the RX to space drops by 5-15 mins. and use NLO.
Carol Noreen Carson, R.Ph.
189
S EC T I O N 8
Apparent Bioavailability in Excess of 100

Percent
On 11 Dec 1997 at 10:57:12
In analyzing some data recently, we ran across a number of test molecules which appeared
to possess systemic oral bioavailability (F) substantially in excess of 100% (i.e., 150-220%).
Our study design was as follows: administer a 30-min i.v. infusion on study day one, and
calculate standard non-compartmental PK parameters from the resulting concentrationtime data. On study day two, administer the same compound by oral gavage, in solution,
and again get PK parameters from the conc.-time data. To estimate F, we used the ratio
of the dose-normalized AUCs for each dosing regimen. (i.e., DNAUCpo/DNAUCiv
*100).
After observing this phenomenon, we re-did several studies with one of the compounds of
interest, lowering the p.o. dose such that it was identical to the i.v. dose. Each time, our
apparent F was on the order of 150-180%.
We have considered several possibilities, including route-dependent enterohepatic recirculation (if absorption is rapid, the liver could see a much larger dose after po dosing, and
more compound could be excreted in bile, leading to increased recirculation) and (less
likely) pulmonary elimination of the compound following i.v. dosing.
Input from the group would be most appreciated. Does anyone else know of examples of
compounds with apparent F this large? We can find no such references in the literature,
but would appreciate any references you may have. Also, are our explanations of the phenomenon reasonable? Are there others we are missing? If so, how would one design an experiment to test the alternative hypotheses? Any input would be helpful - I look forward
to reading your discussion postings on this topic.
Keith Ward
Investigator, DMPK, SmithKline Beecham Pharmaceuticals R&D, King of Prussia, PA
190
[Any (other) suggestion of non-linear pharmacokinetics? Saturable metabolism or

saturable protein binding have the potential to distort the determination of F from AUC
ratio calculations - probably in opposite directions. Non compartmental methods including F from AUC ratio become much less convenient when there is non linear kinetics.
Have you performed dose ranging studies? I would recommend simultaneous fitting of IV
and oral data with if appropriate non-linear (saturable) components. Enterohepatic recycling etc. will also make the 'simple' non compartmental analysis invalid - db]
On 12 Dec 1997 at 15:20:28
I think David Bourne's comments are very good. The only other thing I would suggest is
another way of modeling the data. For example, you might make an iterative Bayesian and
also an NPEM model, in which both regimens can be combined into a single consecutive
regimen. You can also get F from such a mixed IV-PO regimen with this software.
In addition to the basic linear model having an absorptive, central, and (if needed) a peripheral compartment, we are now starting to make nonlinear and larger NPEM models
using the Cray T3E at the San Diego Supercomputer Center. There you can make your
model by typing the ODE's, etc, and running it.
90033
[Roger has added the dimension of population analysis along with simultaneous iv/po
modeling. The model would need to 'also' include a nonlinear component. Modeling individual subject data may not require a Cray - db]
On 12 Dec 1997 15:42:04
I recall that F values greater tna 100% also have been seen with oral administration of
ethanol if the rate of administration is rapid enough.
Bruce Charles, PhD
School of Pharmacy, The University of Queensland, Brisbane, Qld, Australia 4072
191
On 12 Dec 1997 12:46:19
isn't it possible that there is a new metabolite, which is only built following the peroral
route of administration, and that this metabolite interferes with the analytic ?
Ralph Quadflieg
Pharmazeutische Technologie und Biopharmazie, Universitaet Bonn, An der Immenburg
4, 53121 Bonn
On Fri, 12 Dec 1997 09:49:09
I agree with David's suggestion to think of non-linearities in first-pass extraction after oral
administration. If the rate of absorption after the oral dose is faster than the IV rate of input and the drug has saturable elimination then the AUC after the oral dose can be greater
than after IV. This has caused much confusion from the naive interpreters of AUC when
comparing IV and oral doses of ethanol.
Nick Holford
http://www.phm.auckland.ac.nz/Sta/NHolford/nholford.htm
On 15 Dec 1997 at 10:49:45
Another way to increase the oral AUC in the experiment described (one iv dose and oral
dosing the next day) is to inhibit metabolism with the exposure on the first day. Dichloroacetate, for instance, is known to inhibit its own metabolism following a single dose to humans. I think that is described in Curry, S. H., Lorenz, A., Chu, P., Limacher, M. and
Stacpoole, P.W. (1991). Disposition and pharmacodynamics of dichloroacteate (DCA) and
oxalate following oral DCA doses Biopharm. Drug Disp. 12, 375-390.
Obviously there are many experiments that would easily check this hypothesis, like reversing the order of dosing or only using naive animals.
Hugh Barton
PBPK Modeling, ICF Kaiser
192
On 15 Dec 1997 at 10:50:00
I agree with some hypothesis about enterohepatic recirculation, but I think that maybe
you need to consider changes un half-lives and in MTR. You do not spicify if they change,
but modelling combined IV-PO could be an interesting way to consider.
One more thing: All population came from same sex?
Carlos Ramos Mundo MS, MEXICO.
On 16 Dec 1997 at 10:54:54
There is one other thought about how this may have occured. Years ago when we were doing our curve fitting we noticed that occassionally we calculated a negative mean residence
time when we used a polyexponential to fit our blood level curve. Graphically it looked
like we had a good fit (Figure 1 in the reference listed below), however, when we plotted
our curve beyond our last data point, we noticed the curve did not assymptotically approach zero from above the axis, but dipped below and then came back up to zero (Figure
2). This can happen if the pre-exponential coecient (A) of the smallest exponential coefficient (alpha) becomes negative. If the curve fitting program does not appropriately parameterize the values being fit, you can have those types of results. See our short communication in Biopharm & Drug Disposition 9:579-586 (1988).
Ronald A. Herman, Ph.D.
On 18 Dec 1997 at 10:38:13
It would help much if you would give more details on your experimental settings including
sampling scheme and the limit of quantification of your assay method. Also important is
how did you calculate AUCs. The only examples of abnormally high F I know were not related to any pharmacokinetics, but rather to experimental methods and data analysis.
193
On 18 Dec 1997 at 10:40:40
Dear Keith
You comment:
In analyzing some data recently, we ran across a number of test molecules which appeared to possess systemic oral bioavailability (F) substantially in excess of 100%
(i.e., 150-220%). Our study design was as follows: administer a 30-min i.v. infusion
on study day one, and calculate standard noncompartmental PK parameters from the resulting concentration-time data.
Have you considered adsorption or absorption of the substance onto/into the infusion tubing. Adsorption can be important for biological molecules (eg proteins like insulin), and absorption can be important for lipophilic compounds. This would result in a lower dose being administered and hence an apparent lower F from iv than PO.
After observing this phenomenon, we re-did several studies with one of the compounds
of interest, lowering the p.o. dose such that it was identical to the i.v. dose. Each
time, our apparent F was on the order of 150-180%.
This is the right sort of order of magnitude for sorption interactions.

Steve Duull
194
S EC T I O N 9
Apparent Volume of Distribution with One

Capacity Limited Process
On 6 Aug 1997 at 11:13:40
Recently, I have come across a situation involving nonlinear clearance of a drug in which
the volume of distribution is not well defined. Any clarification will be greatly appreciated.
The rate of elimination for a drug eliminated by only one capacity-limited process is given
by:
dCp
Vma x Cp
=
dt
Km + Cp
or
dXe
Vma x V Cp
=
dt
Km + Cp
It is apparent from this relationship that the Cls of a drug is dependent on V. The question then is: What is the definition of V ? Is it the volume of distribution in the central
compartment, volume of distribution during the terminal phase or some other combination of terms especially if multi-compartment processes are involved ?
Roseline Pardue
On 11 Aug 1997 at 13:54:48

It is apparent from this relationship that the Cls of a drug is dependent on V.
If you choose this parameterization the volume you want is the central compartment
volume. Most people who have used this kind of model in PK have preferred to define
Vmax in units of mass/time rather than conc/time as you have done.
If you define X as the amount of drug in the central compartment and Vmax in mass/time
units then:
195
dX
Vma x Cp
= RateIn
(
dt
Km + Cp )
then define Cp as X/V you can write:
dCp
Vma x Cp
= RateIn
/V
(
)
dt
Km + Cp
In this case it is obvious that V must refer to the central compartment volume because the
DE is describing the central compartment rates.
Nick Holford
On 11 Aug 1997 at 13:58:30
I have tried to clarify this problem on a recent paper: "Clearance, Turnover Time, and
Volume of Distribution" published by Pharmacological Research, 35, 189-193, 1997.
Aldo Rescigno
On 13 Aug 1997 at 10:03:43
Your post reminds me of a productive debate that I had with Nick Holford in a thread
that is still available on the BIS Computational Biology Forum at
http://www.BioInformaticsServices.com/rphair/bis/resources/forum.
The thread is called " Compartmental model parameterisation" and deals primarily with
the relative merits of Clearances and rate constants for characterization of PK systems.
You might find it informative. I know I learned a lot from Nick in the course of that discussion.
To answer your question, though, appears to require only that you think about the source
of the V in your equation. You start with dCp/dt on the left hand side, where Cp is the
196
plasma concentration of the drug. You set this equal to the Michaelis-Menten capacitylimited elimination, VmxCp/(Km+Cp).
You do not give a definition for Xe, and I think you might find a clear answer to your question by being precise in your definitions. One way to approach this is to recognize that
mass is conserved, so Vp(dCp/dt) elimination flux (units of , say, umole/hour), where Vp is
the plasma volume. The elimination clearance, Cle, is then the ratio of this flux to the
plasma concentration:
CLe = (EliminationFlux)/Cp
Your post implies that the left hand side of your second equation represents the Cle, so
dXe
dCp
Vp Vm
/Cp = CLe = (EliminationFlux)/Cp = Vp
/Cp =
dt
dt
Km + Cp
Consequently, the V in your equations appears to be equal to Vp, the plasma volume.
http://www.bioinformaticsservices.com
197
S EC T I O N 10
AUCt Greater than AUCinfinity

On 7 Apr 1997 at 22:04:00
A question for anyone with the patience for a newcomer to pk/pd. In a standard study
comparing blood levels of a brand name and generic drug, is a possible to get values for
aucinfinity that are less than the values obtained for auct?
Bill McNaughton
On 9 Apr 1997 at 12:47:11
No, it is not possible to have values of AUC(0-inf) < AUC(0-t).

AUC(0-inf) = AUC(0-t*) + C*/ke where C* is the last measured concentration at time (t*)
and ke is the terminal elimination rate constant. My guess is that ke was entered as a negative value. ke is determined from the slope of the terminal linear portion of the LN
(Conc) vs time curve. The slope will always be negative since concentrations are declining.
It is sometimes an art in determining which points to use in determining the terminal
slope. The terminal elimination rate constant term implies decreasing concentrations and
therefore the negative is not required (ke is always positive, -(slope))
David Nix
On 9 Apr 1997 at 12:47:30
The partial area under the curve (AUCt) is the area from t=0 to t=t. AUCinfinity is the area
from t=0 to t=infinity. Since there can be no negative contributions to the AUC at any
time after t (or before t, for that matter) AUCinfinity is always greater than AUCt.
Of course, one might make the mistake of plotting the data on linear, instead of semi-log,
paper, and then extrapolating a fast (apparently terminal) exponential through the horizontal axis and thus appear to start accumulating negative contributions to AUCinfinity. It
198
should be clear however that the real blood concentration can never be a negative number,
so the AUC can only increase as the integration is carried out toward infinity.
Bob Phair, Ph.D.
On 9 Apr 1997 at 12:47:45
It is possible and is also incorrect. Check your rules for determining half life and extrapolation to infinity.
Steve Bramer
On 9 Apr 1997 at 12:48:37
You have raised a very interesting point. I too have come across occasions when AUC(inf)
values were lower than AUC(t). We need to clearly define the AUC(t) values. Is this the
AUC up to the last validated measurable plasma concentration [C(last), I call the corresponding AUC, AUC(last)] or is it the AUC up to the last point which is below the limit of
quantitation [considered zero in AUC calculation] which I call AUC(all).
It would be highly unusual to have AUC(last) larger than AUC(inf). However, it is possible
for AUC(all) to be larger than AUC(inf). This occurs when time span is large between the
last validated plasma concentration in the disposition phase and the next sample with
concentration below quantitation.
The above is dicult to explain in words. You will get a better appreciation if you draw a
figure. I would be happy to fax you one.
As a note, I don't particularly like to use AUC(inf) for drugs with short half lives (T1/2 = <
12 hours). The reason for this is one single concentration [C(last)] in the beta phase has a
high influence on the AUC(inf) values since AUC(inf) = AUC(last) + [C(last)/(0.693/T1/2)].
It is simply better to determine AUC(last) with most sensitive assay and taking blood samples for a time period exceeding 4*T1/2.
199
AUC(inf) is more appropriate for drugs with long T1/2 (>24 hours) provided that the ratio
of AUC(last)/AUC(inf) exceeds) 0.80.
I hope the above will stimulate discussion on AUC determinations since this parameter is
critical in bioavailability assessment.
Aziz Karim
On 10 Apr 1997 at 13:31:57
Bill,
While it is true that the actual AUC(inf) cannot be less than the actual AUC(t), it is possible to calculate an AUC(t) value that is larger than the calculated AUC(inf) value depending on the sampling scheme relative to the half-life, as Dr. Karim discussed.
As a follow-up to his note on the potential inaccuracies of the calculation of AUC(inf) for
compounds with short half-lives, if variability of the low concentrations is an issue,
AUC(inf) could be extrapolated from a predicted C(last) at the time of the last measurable
concentration based on the half-life (beta) regression. With this method, the data used to
estimate half-life would be weighted equally in the extrapolation to infinity. This method
assumes that there are adequate data to estimate the half-life relatively accurately.
Jo Cato
On 10 Apr 1997 at 13:34:03
AUCt cannot exceed AUCinfinity since AUCinf = AUCt + C(t)/?z. However, it is possible
to get AUCinfinity < AUC(0-24) or AUC(0-48), AUCall, etc.
If your sampling points in the terminal phase are far apart and your last sample is BQL
(and your program treats BQL samples as zero), then ?z may be larger than the slope connecting the last 2 points which are C(t) and 0. This will cause AUCinf to be less than
AUC0-24 because in the calculation of AUCinf, zero is not used.
Brinda K Tammara
Otsuka America Pharm. Inc., Rockville, MD-20850
200
On 10 Apr 1997 at 13:34:26
As indicated by several replies generated from the inquiry as to whether one can get values
of AUC(0-inf) which are less than AUC(0-t), the answer is that in theory NO. However in
practice you may come across data which suggests that this is the case. Apart from the obvious error in calculating AUCs. I assume you have used the correct formula for
calculating the area of trapezoids, or as David Nix pointed out you may have used -ke
rather than the absolute value of ke to calculate AUC(t-inf). that is if you have devised you
own routine for calculating the parameters. Alternatively the problem may reside in the
software package you are using in that some software may calculate AUC(0-inf) either
using the exponential fitting parameters or alternatively use the expected concentration at
time 't-last', derived from the terminal rate constant as opposed to observed value whilst
AUC(0-t) have been calculated using observed values. Bit complicated but I hope it is
clear.
Faruq H Noormohamed
201
S EC T I O N 11
Blood flow or Perfusion

On 24 Apr 1997 at 11:10:16
I would like to pose a dierent question to the entire group for brainstorming and learning:
In relation to drug delivery and particularly to pharmacokinetics, what would be the definition of "Blood flow" versus "perfusion"? Are they the same? Or are they dierent? If different what is their relationship or interdependence?
Alfredo R. Sancho,
USC PK-Imaging Ctr., Los Angeles, CA
On 25 Apr 1997 at 11:56:57
From a clinical point of view, you could have blood flowing through a vessel which is distally obstructed and therefore have no perfusion beyond the obstruction. So, you can
have blood flow without perfusion. The converse however is not possible.
Oscar Linares
On 28 Apr 1997 at 11:06:29
About the question on blood flow and perfusion it should be noted that are two dierent
concepts. One is related to the passage of blood trough a vessel, that is a necessary condition, but not sucient to have perfusion, since an adequate pressure is needed to achieve
percussion. So both are physical terms related to cardiovascular physiology, but by no
means have clinical or physiological equivalence
Fermin Valenzuela, Dept. of Pharmacology, Faculty of Medicine, Universidad Nacional
Autonoma de Mexico
202
On 28 Apr 1997 at 11:18:27

In relation to drug delivery and particularly to pharmacokinetics, what would be the
definition of "Blood flow" versus "perfusion"?
Blood flow: The movement of blood within the blood system as a direct result of cardiac
output.
Perfusion: The movement of blood from the CV system into and through organs or tissues.
Are they the same?
Or are they different?
They are dierent.

If different what is their relationship or interdependence?
Perfusion is dependent upon blood flow supplying the perfusate (blood, plasma, leukocytes, etc.) to the organ or tissue being perfused.
Louis P. Blatzheim
On 28 Apr 1997 at 11:19:04
Hi, I am very interested in these questions as I am working on a study of peripheral vascular disease using fluorescent dyes.
In relation to drug delivery, I think blood flow and perfusion can be very dierent. Perfusion is dependent on factors such as permeability, diusion, and the surface area of the capillaries, in addition to the flow to the region. Blood flow would be dependent on cardiac
output and heart rate, and local autonomic control of vasoconstriction.
I am now interested in whether combined pharmacokinetic information from an intravascular indicator dye and a permeable dye can give information on both flow and permeability. Any comments on this idea would be appreciated. Specifically I am working with
sodium fluorescein (permeable) and indocyanine green (intravascular).
Deborah Oh
University of Illinois at Urbana-Champaign
203
On 28 Apr 1997 at 11:18:40
From the perspective of a cardiovascular physiologist, blood flow is well-defined. It is a

measure of the volume of blood passing a given point in the circulation per unit time. It
has units of, say, ml/min. When a "perfused organ" preparation is used, we mean simply
that we are (or an anesthetized animal is) pumping blood into the arterial side of an organ's
or tissue's vascular system.
So I would ask, when used in the context of pharmacokinetics, what are the units of "perfusion"? Or even, what is the definition of perfusion?
Oscar's point is well-taken in that some portion of a tissue may not be perfused because of
an upstream obstruction, but I'd argue that that portion of the tissue is also without blood
flow.
So you cannot deliver a drug (at least by a vascular route) to a tissue that receives no blood
flow and is thus "unperfused".
On 28 Apr 1997 at 11:20:41
Webster definition of perfusion: the act of pouring over or through, especially the passage
of a fluid through the vessels of a specific organ.
Not being a pharmacokineticist but a radiologist working on perfusion measurement from
images, I do not know the field enough to answer your question-the pharmacokinetic
sense of perfusion. The concept of perfusion has become controversial, especially with the
growing application of MR and CT for perfusion measurement.
Perfusion to an organ is determined by complex physiologic/anatomic processes: blood
pressure, velocity, capillary morphology, capillary permeability, oxygen and nutrient demands. The definition of perfusion has varied depending on the field of interest: physiologist, radiologist, pathologists, cardiologist, etc. Perfusion in the classical physiological
sense is blood circulation: it is measured by total blood flow per a unit mass or volume of
204
tissue (e.g. ml/min/100g). For example, a single organ such as the kidney with a single
blood supply, the blood flow into the kidney is measured and divided by its mass. In this
definition, blood flow may be synonymous with perfusion. But we must remember that
classical perfusion measurement techniques are based on terminal deposition (microsphere) or washout (radionuclide) of tracers and hence only considering the component of
blood flowing in the capillary bed. This approach excludes the blood which transits without exchanging with the organ.
This definition also should exclude physiologic blood-tissue exchange which is frequently
confused with perfusion. In practice, however, the blood-tissue exchange is an important
part of drug transport to an organ and very dicult to separate from overall drug transport measurements.
K. Ty Bae, MD, PhD
On 28 Apr 1997 at 11:21:45
My understanding is that perfusion relates to flow of blood to exchanging capillary beds

and total blood flow is exactly that. The dierence is particularly important in tissues
such as the skin where there are considerable numbers of a-v shunting vessels.
Laurent Rivory
On 29 Apr 1997 at 09:55:11
There is an extensive literature on using permeable and inpermeable markers to get information on blood flow and permeability (as well as markers that enter parenchymal cells).
You could start with names like Carl Goresky, Ken Zierler, and Jim Bassingthwaighte. As
you might imagine it is easy to spell Jim's last name incorrectly, and I probably have done
so here. You could also look at an old book by Niels Lassen and William Perl titled Tracer
Kinetic Methods in Medical Physiology, Raven, 1979.
Regarding your distinction between blood flow and perfusion, I would argue you are using
perfusion to signify extraction. I personally don't think perfusion is well-defined, but if it
were it ought to have the same units as blood flow and might represent the fraction of cardiac output that is delivered to a particular tissue or organ.
205
I suspect, however, that this debate is going to generate more heat than light.
On 29 Apr 1997 at 09:55:27
Dr TyBae says, in part:

Perfusion to an organ is determined by complex physiologic/anatomic processes: blood
pressure, velocity, capillary morphology, capillary permeability, oxygen and nutrient
demands. The definition of perfusion has varied depending on the field of interest:
physiologist, radiologist, pathologists, cardiologist, etc. Perfusion in the classical
physiological sense is blood circulation: it is measured by total blood flow per a
unit mass or volume of tissue (e.g. ml/min/100g). For example, a single organ such as
the kidney with a single blood supply, the blood flow into the kidney is measured and
divided by its mass. In this definition, blood flow may be synonymous with perfusion.
But we must remember that classical perfusion measurement techniques are based on terminal deposition (microsphere) or washout (radionuclide) of tracers and hence only considering the component of blood flowing in the capillary bed. This approach excludes
the blood which transits without exchanging with the organ. This definition also
should exclude physiologic blood-tissue exchange which is frequently confused with perfusion. In practice, however, the blood-tissue exchange is an important part of drug
transport to an organ and very difficult to separate from overall drug transport measurements.
Two points can be made here. First, if perfusion is defined as "organ blood flow", then it's
determined by arterial pressure, venous pressure, and the organ's vascular resistance. Resistance is usually dominated by the arterioles. Under this definition, perfusion is independent of velocity, capillary morphology, capillary permeability, and oxygen and nutrient demands. Second, classical perfusion measurement techniques are not entirely limited to microspheres, or radionuclide washout. It would be reasonable to ague that perfusion could
also be measured by a flowmeter on the incoming artery.
So, it seems to me that perfusion is organ blood flow, perhaps corrected for a-v shunts as
was pointed out by another post in this thread. As such it has little (I would say nothing)
to do with blood-tissue exchange. This may be what Dr TyBae means by, "This definition
also should exclude physiologic blood-tissue exchange which is frequently confused with
perfusion." Organ blood flow or perfusion is, of course, a crucial determinant of drug delivery to the capillary beds. Once there, however, the drug's chemical properties and the available transport mechanisms will determine its extraction. At a very detailed level, one must
206
also be concerned with the issues of flow-limitation, but once in the interstitial space, cellular uptake, too, is independent of blood flow. Thus Dr TyBae is correct that blood tissue
exchange is an important element of drug delivery, but mixing the concepts of perfusion
and extraction can only lead to unending semantic wars, as is apparently the case in radiological usage currently.
207
S EC T I O N 12
Blood Volume
On 9 Oct 1997 at 10:39:32
Would anyone be able to supply me with a formula (and hopefully a reference) for determining blood volume> Perhaps based on height and weight/ body surface area, lean body
mass? Any help is greatly appreciated. Thanks in advance.
Bob Dunn
On 09 Oct 1997 20:15:50
I usually use 65-70 ml/kg but it depends on the species

Andrew Fowlie
On 10 Oct 1997 08:14:33

You will find blood volume (man: 7.5% of body mass) and other physiological parameters
for man, rodents, rabbit, dog, and monkey in: DAVIES,B. and T.MORRIS: Physiological
parameters in laboratory animals and humans, Pharm. Res. 10, 1093-1095, 1993.
Hans Markus
On 10 Oct 1997 10:31:06
The general rule is 8% of body weight. Thus 80 mL of blood per kg body weight
Rob Hunter
208
On 20 Oct 1997 at 12:26:06
I've found the Geigy Scientific Tables (were published by Ciba Geigy before the merger;
now?) useful for human blood volume as functions of the sort of parameters you mention.
I think o.and it's one of the later volumes which treats the subject in some detail, with a
choice of formulae and secondary references.
DuncanMFE
209
S EC T I O N 13
Calculation of F and PK/PD Modeling

On 5 Sep 1997 at 10:54:12
I would like to get your opinions on the following questions.

First one is on the calculation of relative bioavailability.
To calculate the relative bioavailability of a oral formulation in individual subject, we can
use (1) the ratio of individual AUC from oral dosing to average AUC from IV dosing to a
group of subjects or (2) the ratio of individual AUC from oral dosing to individual AUC
from IV dosing. I call second method self-comparison method. I would like to know
which method is more accurate? Any statistical or physiological justification?
Second question is on PK/PD correlation.
I would to know how to deal with PK/PD correlation problems in the situations such as
plasma concentration measurement and ecacy determination on dierent time intervals
(PK in hours and PD in days) or dierent dosage regimen for PK and PD (PK-single dosing and PD-multiple dosing). Your answers or suggestions for references will be greatly appreciated.
Tony Lee
On 8 Sep 1997 at 10:20:45
The topic is more complicated than is suggested in this question. There can be hardly any
debate about the question which method should be used to calculate the relative (or absolute) bioavailability FOR AN INDIVIDUAL: method (2). The reason is simple: AUC comparison is based on the assumption that clearance is constant. Since clearance is, in general, a pharmacokinetic parameter with relatively high inter-individual variability, it is essential that AUC of the same individual are compared.
210
However, the question is more complicated if you are interested in the 'best' (unbiased) estimate of 'average' bioavailability of a group of subjects (or, in terms of population PK, a
typical value of bioavailability of the population), and its variance. In this case, some assumption on the statistical distribution are necessary. In my opinion, it is both realistic
and practical to assume a log normal distribution of the pharmacokinetic parameters. The
calculation is easy: (a) calculate the bioavailability of each individual subject (ratio of doseadjusted individual AUCs) (b) calculate the mean and sd of the log(base e)-transformed ratio's (c) mean bioavailability is inversed of log-mean (d) coecient of variation (CV, expressed as fraction) is the sd of the log(base e)-transformed ratio's (e) sd of bioavailability
is product of mean bioavailability and CV.
If AUCs from the same individual are not available, the aforementioned procedures don't
work correctly! In this case a dierent approach is necessary.
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, Groningen, The Netherlands
On 9 Sep 1997 at 10:46:11
What you refer to as the "self-comparison method" is the better way to assess the bioavailability (F) of a drug in an "individual subject". The ratio of AUCpo / AUCiv both obtained from the same individual (under all the same conditions, other that route of administration) would control for between-subject sources of variance which would have an
equivalent influence on the AUCs regardless of the route of administration. Such sources
of variance would include for example, the apparent distribution volume of the drug and
it's rate of clearance.
The only instance this might not be true is when the error of measurement is much
greater than individual dierences in the post-absorptive determinants of AUC. But if
that were true, the whole question of "the relative bioavailability of a oral formulation in
individual subject" would be compromised. If it's not already obvious, the best method is
to assess the AUCpo / AUCiv for each individual in a group of subjects and then describe
bioavailability by descriptive statistics.
211
By the way, there is at least one important drug for which the comparison of AUCpo / AUCiv is not appropriate for assessment of its bioavailability. (hint: it accounts for > 5% of
the total American caloric intake).
R. Thomas Gentry, Ph.D.
Oce of Collaborative Research Activities, National Institute on Alcohol Abuse and Alcoholism, Willco Bldg., Suite 400, 6000 Executive Blvd., Bethesda, MD, 20892-7003
On 15 Sep 1997 at 15:12:58
Again, the situation is more complicated than in my first answer!

My first answer to the PharmPK group was an approximation, which will be suciently accurate in most cases. Here is a more complete answer, with the exact solution.
The only, almost complete reference to log normal distributions can be found in:
Biostatistics in Pharmacology (volume I, pp. 544- ) by AL Delaunois, LJ Martin, E Olbrich, AA Weber Pergamon Press - Oxford 1973 (ISBN 0 08 016556 7) (series 'International
encyclopedia of pharmacology and therapeutics)
According to this reference, the relationship mentioned in my note to the PharmPK
group is only valid for the case CV is small.
For variance, the following relationship is given in the aforementioned reference (symbols
modified to text):
var = s^2 = ln(1+CV^2)
where var is the variance of the ln-transformed data, s is the standard deviation of the lntransformed data, and CV is the coecient of variation (^2 = square)
If CV is small, var is almost equal to CV^2.
E.g.,
if s = 0.1, it follows that CV = 0.10025,
if s = 0.25, then CV = 0.25396
212
if s = 0.4 (rather large!), CV = 0.41655

Note: always use 'ln', natural logarithm, base e (using logarithms with base 10 requires co
factors; I don't like them, and they should be banned from the whole field of pharmacokinetics).
Johannes H. Proost
On 17 Sep 1997 at 10:57:56
About bioavailability. The fraction absorbed can also be computed directly from a mixed
dosage regimen containing both IV and PO dosage in individual patient regimens. This
can be done in both parametric and nonparametric population models, using iterative
Bayesian and nonparametric EM software for such modeling. This avoids comparison of
AUC's, obtained possibly under diering clinical circumstances, and permits it to be done
in the patients of interest, in their often changing clinical circumstances.
90033
http://www.usc.edu/hsc/lab_apk/
213
S EC T I O N 14
Collinearity and Mixed Eect Models

On 30 Sep 1997 at 11:04:55
Does anyone have any references on what is the impact of collinearity among predictor
variables in a mixed eect model (either linear or nonlinear)?
Peter L. Bonate, Ph.D.
Hoechst Marion Roussel, Clinical Pharmacokinetics, P.O. Box 9627 (F4-M3112), Kansas
City, MO 64134
On 20 Oct 1997 at 12:25:52
I think that this is a good question that I would also like to see further discussion about. I
have not read any literature specifically addressing the eects of collinearity in nonlinear
systems. For the linear system, almost any good stats textbook will provide an adequate
description.
For the linear model:
Multicollinearity
Where explanatory variables are highly correlated the following may occur:
1.
Coecients may have large standard errors, since large changes in one coecient can
be compensated for by equally large changes in another. Hence very dierent coecient values may result in nearly the same sum of sq.
2. May result in product moment correlation coecients (r or r^2 values) that are inappropriate (often constricted). For example regressing two covariates, that have significant correlation with each other, against a dependent variable, often results in higher
r^2 values when each is considered alone but the resultant model will often have a
lower r^2 value when both are considered together.
214
3.
Significant rounding errors may be introduced into the system.
In terms of non linear models r^2 values are not usually considered and hence point 2 will
be will be seen in other ways. Obviously the correlation between coecients can be addressed prior to undertaking non-linear regression.
I don't think the mixed eect model will alter the eect of multicollinearity. I do not see
how accounting for random eects will change the influence of multicollinearity (or perhaps "multi-co-non-linearity"). However, it seems probable that estimation of the random
eect component will be in error if there is significant correlation between the covariates.
There will obviously, also be error in the coecients that describe these covariates.
I hope these comments are useful. I look forward to the comments of others.
Steve Duull
On 21 Oct 1997 at 10:10:07
Even when documented eect of collinearity in nonlinear models is quite a few, there is a
point of view that may help:
"Collinearity in nonlinear models could cause that parameters estimates in iterative methods (like Marquardt), present an "apparent" low ss, however it is possible that ss surface is
deformed by covariates, then predictors could be far from real values. Maybe a procedure
to try to avoid this eect is to use partial correlation and other analytical procedure such
as quadratical or transform covariates to get ride of collinearity"
As far as we concern, we try to several transformations to avoid collinearity, but the final
eect is a strong tendency in residuals, at least in data that shows two- or onecompartment behavior. The eect is more evident when you try with flip-flop data.
Nowadays, we are trying with dud's method and it presents an error in simulation approximation of 5 -12 % in final estimates. Hopefully we will try this method with real data in
next week.
It is important to point out that the main idea is to get a procedure to reduce collinearity
eects, even when is probably to derive in handling experimental factors.
Carlos Ramos Mundo. M.S.
215
S EC T I O N 15
Compartmental Modeling and Population PK

On 20 Oct 1997 at 12:26:55
Lately, there has been a lot of trac in this discussion group about compartmental models,
i.e., how multi-exponential fitting relates to compartmental models, the advantages of
compartmental modeling, its disadvantages, etc.
In general, compartmental models get a lot of bad press and kineticists are reluctant to use
them in drug development. People talk about the issue of the number of compartments,
non-identifiability, trying to intrepret parameter constants, etc and because of this, most
pharmacokinetic analyses in drug development center on non-compartmental analyses assuming that non-compartmental models are model-independent (a wrong assumption).
Population pharmacokinetics has the same disadvantages of classical compartmental models (assumption of a specific model which may be non-identifiability) in addition to others
that are often not discussed (collinearity among predictor variables being the most egregious). Yet no one questions a pop pk analysis to the same extent as classical compartmental modeling, even though pop pk analyses often have fewer samples per subject albeit
with greater numbers of subjects. It is as though having greater numbers of subjects gives
a pop pk model greater validity than doing compartmental analysis on a data-rich data set
with fewer subjects.
Any comments on this? Just food for though for the AAPS focus group next month.
City, MO 64134
On 21 Oct 1997 at 10:09:53
I really don't think there is much dierence in philosophy among "classic" (multisampling) and population (sparse sampling) approaches in the caution that needs to be ex216
ercised against applying the "wrong" model (with or without covariates). If the compartmental model is inadequate, the intrapatient variance (SIGMA) estimated in parametric
population modeling is greatly inflated (although other sources obviously contribute such
as assay error, inaccurate dosing and sampling times, etc). For ours, when we do population
modeling we are very aware of the pitfalls of implementing an inappropiate model, e.g.
when there area total of 2 or 3 samples taken at dierent post-dosing times perhaps over
several dosing intervals. We usually screen 1 and 2 (or, occasionally, 3) compartment models
and examine weighted residuals and parameter estimates and SEs of estimation. The latter
is important when looking at possible multicollinearity of covariates. If an appropariate
model-building strategy is used, e.g. individual screening of covariates, stepwise addition of
"significant" (P<0.01?) factors followed by backwards elimination, then the possibilty of
variables "masking" one another is greatly reduced (but it can still happen). We have no
problem with the use of compartment models, as compared with other representations of
the data since they do have a degree of physiological relevance. In NONMEM estimates
of the more relevant primary parameters of interest (clearances and volumes) can be
sought directly by reparameterising those dreadful compartmental rate constants.
Bruce CHARLES, PhD
School of Pharmacy, The University of Queensland, Brisbane, Qld, Australia 4072
On 21 Oct 1997 at 10:11:36

In general, compartmental models get a lot of bad press and kineticists are reluctant
to use them in drug development.
Population pharmacokinetics has the same disadvantages of classical compartmental models (assumption of a specific model which may be non-identifiability) in addition to
others that are often not discussed (collinearity among predictor variables being the
most egregious). Yet no one questions a pop pk analysis to the same extent
IMHO those who discard compartmental approaches have a dierent philosophy of

where the real problems lie. It seems to me that they think there is some kind of "true"
and "objective" answer uncontaminated by assumptions which can be achieved by invoking the "non-compartmental" mantra.
Population modellers have sidestepped/overcome this particular intellectual hurdle and
seem to find additional insight from applying models (whether individual or population)
and can live with the assumptions and uncertainties.
217
I can assure you that the population modelers I know frequently discuss the problems
with the technology and are continually seeking better solutions. From a limited perspective as an author, referee and editor of papers dealing with population models I would say
that population models come in for a lot of peer criticism during the manuscript review
process. This is valuable for authors and referees but readers of published articles may not
appreciate what has gone on before the MS appears in print.
Nick Holford
http://www.phm.auckland.ac.nz/Sta/NHolford/nholford.htm
218
S EC T I O N 16
Creatinine Clearance and IBW in Small

Patients
On 25 Feb 1997 at 12:35:54
I am always running into non-pediatric patients, usually elderly, but could be any age
group, who do not fit (naturally!) the standard 5 feet tall + scenario OR have ABW (actual
body weight) that are <45.5 kg or 50 kg for male or female, respectively. Someone recently
(and of course I can't find the formula!) had a CrCl calculation incorporating serum albumin for patients with low values, but this is NOT the patient population I am looking for
(though some may fit into this category). Any suggestions?
Marc Semprebon, RPh
DHMC, Lebanon, NH 03756
On 26 Feb 1997 at 16:20:32
At least part of the problem you appear to be having may be helped by using a suitable
model for size. This may help particularly with smaller than average people e.g.
CL = CLstd x (Wt/Wtstd)^3/4
where CLstd is the CL in a 'standard' size person with weight Wtstd. You can use total
body weight, ideal body weight.
See this for details:
Holford NHG. 1996 A size standard for pharmacokinetics. Clin Pharmacokin, 30, 329-332
Nick Holford
219
S EC T I O N 17
Determining CYP3A4 activity in vitro

On 3 Sep 1997 at 10:15:09
We are looking for an index reaction to determine the activity of cytochrome P450 isoform 3A3/4 in human liver microsomes (in vitro). Currently we used dextromethorfan Ndemethylase as index reaction for CYP3A4. However, a current article suggests that also
CYP2E1 is involved in the formation of 3-methoxymorphinan and therefore dextromethorfan N-demethylase is not a good index reaction.
Does anybody have a GOOD suggestion how to determine the CYP3A4 activity in vitro?
Alex Hemeryck
Pharmacist, Heymans Institute of Pharmacology, University of Ghent, Medical School
De Pintelaan 185, B-9000 Ghent
On 4 Sep 1997 at 10:21:03
Hydroxylation of testosterone to 6-hydroxytestosterone is commonly used as an index reaction for CYP3A4/5 in human liver microsomes. Also, recently it has been reported that
alprazolam 4-hydroxylation is predominantly metabolized by CYP3A3/4. Erythromycin
N-demethylation and midazolam hydroxylation are other common probe reactions.
Nipedipine is another substrate for CYP3A4. Following references might give more information.
Alprazolam metabolism in vitro: studies of human, monkey, mouse and rat liver microsomes, von Moltke, LL, Greenblatt, DJ, Harmatz, JS, Shader, RI; Pharmacology, 1993, 47,
268-276
Characterization of six in vitro reactions mediated by human cytochrome P450: Application to the testing of cytochrome P450-directed antibodies, schmider, J.; Greenblatt DJ,
220
von Moltke, LL; Harmatz JS, Duan Sx, Karsov D, Shader RI, Pharmacology, 1996, 52, 125134
Cytochrome P450 isoform inhibitors as a tool for the investigation of metabolic reactions
catalyzed by human liver microsomes, Bourrie M, Meunier V, Berger Y, Fabre G, J. Pharm.
Exp. Ther. 1996, 277, 321-332
Also, you can get some information at the Glaxo Wellcome drug metabolism guide on the
web at http://www.glaxowellcome.co.uk/science/drugmet/index.html
Chandrani Gunaratna, Ph.D.
Senior Research Chemist, Bioanalytical Systems, 2701 Kent Avenue, West Lafayette, IN
47906
On 4 Sep 1997 at 10:22:10
I think you should read the article of Buening et al. "Activation and inhibition of benzo(a)pyrene and aflatoxine B1 metabolism in human liver microsomes ....." Cancer research
1981 41: 67-72
Or maybe the article of de Waiziers et al. "Cytochrome P450 isoenzymes, epoxide hydrolase and glutathion transferase in rat and human hepatic and extrahepatic tissues" J Pharmacol Exp Ther 1990 253: 387-394
As far as I know the Cytochrome P450 IIIA4 activity is correlated well with the Erythromycindemethylase (ED) activity (r=0.84, p=0.001).
In addition the midazolam hydroxylation activity was used to measure the Cyt P450 IIIA4 activity.
Ralph Quadflieg, Pharm D
Department of Pharmaceutical Technology and Biopharmacy, Universtity of Bonn, An der
Immenburg 4, D-53121 Bonn, Germany
221
S EC T I O N 18
Digoxin Guidelines
On 9 Feb 1997 at 10:12:51
Our pharmacists would like to find guidelines for digoxin dosing and creatinine clearance.
We would appreciate it if anyone can tell us where we can find this.
B. Miers
Methodist Med Ctr., Peoria, Il
On 10 Feb 1997 at 14:54:17
Drug Prescribing in Renal Failure: Dosing Guidelines for Adults, Bennett WM,
Arono GR, Golper TA, et al. Third Edition. American College of Physicians. Philadelphia, PA. 1994.
Drug Dosage in Renal Insufficiency, Seyart G. Kluwer Academic Publishers. Norwell, MA. 1991.
Both sources have specific references.
G. Arono, M.D.
Kidney Disease Program, University of Louisville School of Medicine
On 10 Feb 1997 at 14:54:34
The dosing of digoxin in renal pts and those with liver disease or CHF is not straight forward. However, some useful information maybe found in a little book by JR White and
MW Garrison entitled Basic Clinical Pharmacokinetics Handbook (it sounds bigger
than it really is) (by Applied Therapeutics, inc)
222
Here are some basic steps:

1.
Determine the size of the loading dose.

Vd x desired level x bioavailability (F)
(Vd and F vary depending on pt condition) (therp level depends on whether we are
treating CHF or arrhythmia)
The loading dose is usually 10 to 15 Ug/kg.
The total loading dose is usually divided into 50%, 25%, 25% parts given 6 hrs apart.
2. Estimate the percent daily elimination (%E). This may be done using the Jellie
method: %E = 0.2 CLcr + 14 ; where CLcr=estimated creatinine clearance in mL/min.
3.
Daily maintenance dose = %E x Loading Dose
However, in practice dosing is adjusted according to clinical response (therapeutic and adverse eects) and serum level.
Nasr Anaizi, PhD RPh
On 11 Feb 1997 at 16:19:13
Try the Third Edition of Michael Winter's Basic Clinical Pharmacokinetics. You should
find it very helpful
John Eddy
223
S EC T I O N 19
Diltiazem HPLC Assay

On 1 May 1997 at 17:58:39
We are working in pk/pd diltiazem in acute atrial fibrillation patients. Could anyone inform me about a validated HPLC technique to determine diltiazem in human serum?
Juan Pablo Ordov=E1s Baines
Pharmacy Service. PK Lab., Hospital Dr. Peset
On 2 May 1997 at 12:35:56
You may wish to consult the following reference with regard to a validated method for diltiazem:
Drug Metabolism & Disposition. 24(1):28-33, 1996 Jan.
Richard A. Sams, PhD
Professor and Laboratory Director, Analytical Toxicology Laboratory, College of Veterinary Medicine, The Ohio State University
On 2 May 1997 at 12:36:17
We developed a validated HPLC method to determine diltiazem and its metabolites in human plasma. The article can be found in Journal of Chromatography (Biomedical applications),
582 (1992) 203-209. It also has the reference for other HPLC methods.
M. Delwar Hussain
School of Pharmacy, University of Wyoming, Laramie, WY 82071-3375
224
On 2 May 1997 at 12:36:26
Here is a reference for diltiazem assay;

High-performance liquid chromatographic assay for diltiazem in small-volume blood specimens and application to pharmacokinetic studies in rats Scully, P., Meehan, E. and Kelly,
J.G. Journal of Chromatography A Volume A729, Issue 1-2, 5 April 1996 page 297-300
47906
On 5 May 1997 at 14:28:20
Virgil Dias at Hoechst Marion (when it was Marion Merrill Dow) published a PK/PD series about IV diltiazem in 1992. He would seem like a reasonable place to start. His article was in Circulation 1992; 86:1421-8.
Dr. Vince Pearson
Drug Information Pharmacist, The Johns Hopkins Hospital, Baltimore, Maryland USA
225
S EC T I O N 20
Dissolution Test for Nicardipine HCl Tablets

On 14 Mar 1997 at 10:58:31
Does anyone out there know how to conduct the dissolution test for nicardipine HCl
TABLET (not capsule, not SR) with ocial method? I have been looking for UPS XXIII,
EP (1997), and JP (1991, English version), BPC (1995? 1996?) but can not find it. The information should include as follows:
Medium; Volume; Apparatus; Time; Procedure and Tolerance
Yung-jin (Frank) Lee, Ph.D.
Clinical/Hospital Pharmacy Dep., Tri-Services General Hospital, #8, Sec. 3, Ting-chow Rd,
Taipei, TAIWAN 100, ROC
On 21 Mar 1997 at 10:34:02
The solubilities of these dihydropyridines tend to be very low so it is unlikely you will find
a traditional dissolution method for nicardipine- ie. you could never maintain a sink condition for USP methods I or II. You may want to look in to a flow-through design or an extraction (two-phase) method. Sometimes surfactants help (SLS or Tween) however, they
will only increase the solubility 2-4X at best and this is still not enough for compounds of
this nature.
Keith Anderson
226
S EC T I O N 21
Drug Use in CVVH and CVVHD

On 19 Mar 1997 at 22:09:49
Does anyone know where I can get hold of information on the use of drugs in CVVH and
CVVHD? i.e. which drugs need their doses to be compensated for because of removal
into the ultra-filtrate etc? I especially need information re allopurinol.
Thanks
Estelle Smith, Paediatric Pharmacist, Shaare Zedek Hospital, Jerusalem,Israel
On 20 Mar 1997 at 09:28:16
Here are some general reviews on the topic:

Reetze-Bonorden et al, Drug dosage in patients during continuous renal replacement therapy. Clinical Pharmacokinetics 24 (5) 362 - 379, 1995
Bressolle et al, Clinical pharmacokinetics during continuous haemofiltration. Clinical Pharmacokinetics 26 (6) 457 - 471, 1994.
Bickley SK, Drug dosing during continuous arteriovenous hemofiltration. Clinical Pharmacy 7: 198 - 206, 1988.
Schetz et al, Pharmacokinetics of continuous renal replacement therapy. Intensive Care
Medicine 21: 612 - 620, 1995.
Cotterill S, Antimicrobial prescribing in patients on haemofiltration. Journal of Antimicrobial Chemotherapy 36: 773 - 780, 1995.
I'm not sure you will find anything on allopurinol but they might help you predict the
likely eects.
Alison Thomson
227
Clinical Pharmacokinetics & Biometrics Unit, Dept of Medicine & Therapeutics, West
Glasgow Hospitals Trust, Glasgow G11 6NT
On 21 Mar 1997 at 10:34:36
Reetze-Boroden P, Bohler J, Keller E. Drug dosage in patients during continuous renal replacement therapy: pharmacokinetic and therapeutic considerations. Clin Pharmacokinet
1993; 24:362-379.
This is an extensive review of published data includes a table of suggested dosage adjustments for a large number of drugs.
On 23 Mar 1997 at 11:09:41
We recently had a patient post chemotherapy who developed acute renal failure. The allopurinol dose was 600mg/day. In our CVVH patients, we use a f-40 filter with convection rates of 1 l/hr and blood flows of 170 ml/min. We have measured aminoglycoside clearance rates of approx 25 ml/min. Using this as a guide, and that allopurinol is dialyzable, we
made an empiric dose reduction of 50 % and followed uric acid levels. The uric acid had
dropped from 15.2 to 10.5 at the time cvvh was started. 300mg/day was given during cvvh
for 2 days. The uric acid was 3.7 at that time. Both cvvh and allopurinol were stopped after
2 days and the uric acid level 3 days later stabilized at 8.7.
William Dager, Pharm.D.,FCSHP
228
S EC T I O N 22
EC50 Software
On 14 Aug 1997 at 13:47:54
I am seeking for a computer program which is able to fit concentration-eect curves of

several experiments with the same drug (e.g. n=6) and to determine an Ec50 +/- s.e.m.,
slope and maximum and to compare it with a dierent experiment (dierent drug or presence of an antagonist; e.g. also n=6) and to determine whether the parameters are significantly dierent or not. Until now, we use a program modified from a program of Waud
which works with a logistic function:
K1 A K2
e = K2
A + K3K2
where e = Eect, A = Concentration, K1 = maximum value, K2 = slope and K3 = EC50
However, the determined s.e.m. is very small, probably because it is determined only by
the deviation of all single points from the curve which is fitted through these points. My
suggestion would be that each individual experiment should reveal an individual
concentration-eect curve (with some error regarding the deviation of the points from the
curve) and then the Ec50 and the other parameters (for n=6) with s.e.m. shold be computed.
Wolfgang Vierling
Institute for Pharmcology, Technical University Munich
On 15 Aug 1997 at 10:35:30
We use SigmaPlot by Jandel Software it has a good curve fitting module that provides a
standard error.
Curt Mazur
IDUN Pharmaceuticals, Inc.
229
On 15 Aug 1997 at 10:36:50
There are many programs which will do this but very few that will take into account the
dierences between individuals. If the latter is important to you then I would recommend
NONMEM. Installation and training in the use of this program will require some eort
but once you have mastered it you will find it has many applications in pharmacological
analysis.
Nick Holford
On 18 Aug 1997 at 15:49:29
You may be interested by the work of Davidian et al. :

Davidian M, Giltinan DM, 1993, Biometrics, 49, 59-73
Giltinan DM, Davidian M, 1994, Statistics in Medicine, 13, 1165-1179
They use a maximum likelihood method to fit each curve, and then an EM-algorithm to
estimate the distribution of the model parameters.
A Turbo Pascal program which implements a variant of this method (applied to the more
simple Michaelis-Menten equation, and without the EM step) is available on my web
page.
Jean Debord
Laboratoire de Pharmacologie, Faculte de Medecine, 2 Rue du Docteur Marcland, 87025
Limoges (France)
230
S EC T I O N 23
Eects of Dilution on PK/PD of

Nondeploarizing Neuromuscular Blocker
On 4 Mar 1997 at 13:07:07
I will be conducting a study of the eects of giving a dilute concentration versus a standard concentration of a NMB. We will be comparing onset times and duration. My question is, in theory, should there be a dierence, and if so what should it be? Keep in mind
that equal doses will be given. Is anyone aware of any studies pertaining to any class of
drug where diering concentrations but equal doses were given?
Scott Farley
On 5 Mar 1997 at 11:38:41
If you already know the parameters for absorption, distribution, binding, metabolism, and
elimination of your drug, it would be a simple matter to calculate (using any of a number
of simulation packages) the expected plasma concentrations for the two dierent dosing
protocols (1-short infusion, high concentration, 2-longer infusion, lesser concentration;
both delivering the same total dose). If the drug was designed for a particular dosing
scheme, a smaller concentration infused for a longer time runs the risk of never reaching
the target therapeutic concentration. This could occur, for example, if drug metabolism or
elimination outpaced absorption.
If your situation is more complex, please repost to the list. Good luck.
Robert D. Phair, Ph.D
231
On 5 Mar 1997 at 11:39:54
To answer your question: I don't expect any dierence in onset time and duration between
a standard concentration and a dilute concentration. If there is any eect, it will be small,
and unlikely to be revealed experimentally.
If a drug is administered intravenously, it will be diluted to a considerable extent before it
is transported via the arteria to the muscles. This dilution will be more pronounced if a
small volume is injected, and less pronounced if a larger volume is injected. As a result, the
concentration profile in the arteria will be less aected by the concentration of the injected solution. Although the steep rise and fall of the concentration during the first minute may be less pronounced than after injection of more concentrated solutions, the average concentration in the arteria will be hardly aected, and therefore also the net transport to the biophase.
However, this is theory, and it would be interesting to test this in practice. I am not aware
of studies performed in this topic, so I also are interested in reactions by others.
It is not clear from your message why you want to perform such a study. Is this a question
relevant to anesthesiological practice, or is it a purely scientific interest. Please give us
more information about the rationale behind your question.
Johannes H. Proost
232
S EC T I O N 24
Experience with MATLAB

On 28 Nov 1997
Can anyone tell me if MATLAB is a good tool for modeling using systems of dierential
equations based on their experience with the program?
Paul Damian PhD,MPH
Rust Environment & Infrastructure
On 28 Nov 1997 14:27:48
I have been using Matlab for PBPK modeling. Using the GUI add-on Simulink, dierential equations can be modeled and linked easily. They can be represented in transfer function or state space form, or you can model the equations yourself.
Two sti system algorithms are available with Simulink, Gear and Linsim. Runge Kutte23
and 45, Adams and Euler algorithms are also available.
There is a Systems Identification toolbox for parameter estimation and a Statistics Toolbox that provides methods for parameter sensitivity analysis and optimization. There are
a couple of IEEE papers that will give you some idea of Matlabs capabilities.
Wada, D.R., Ward, D.D. (1994), "The hybrid model: a new pharmacokinetic model for
computer-controlled infusion pumps," IEEE Transactions on Biomedical Engineering., vol. 41,
No. 2.
Wada, D.R., Stanski, D.R., Ebling, W.F. (1995), "A PC-based graphical simulator for physiological pharmacokinetic models", Computer Methods and Programs in Biomedicine., vol. 46,
pp. 245-255.
Alex MacDonald
233
Graduate Student, Dept of Medicine and Pharmacology and Dept of Automatic Control
and Systems Engineering, University of Sheeld UK
On 28 Nov 1997 15:14:43
I have used MATLAB/SIMULINK for many things, have found it an easy tool to use for
modeling and simulation, and have not felt limited by the software. Some examples: (1)
population PKPD estimation - linearization methods, global two-stage (2) optimal sampling (3) PBPK modeling and simulation (4) nonlinear feedback control (5) ANOVA (6)
EEG signal processing
MATLAB is a command-line, interpretive, matrix-based language with scripts. It has
good graphics and reasonable data handling capabilities. To do simple things, the user can
interact at the command line. To do more complex things, the user needs to write equations in the MATLAB language, store the equations in user-defined subroutines, and call
user-defined subroutines or built-in subroutines where needed. MATLAB can do linear
ODE's.
MATLAB is a general-purpose tool. It has no specific tools for pharmaceutics, as an example.
To be useful for PKPD applications requires extra MATLAB toolboxes. I have used the
toolboxes for Optimization, Splines, Control, and Signal Processing. I would like the toolbox for Stats, although the basic tools are present in the standard package (i.e. Fdistributions)
I have found SIMULINK to be very useful for nonlinear simulation, although this is also
an extra package. SIMULINK is a graphical simulator, with about 6 dierent integration
routines (i.e. gear, rk45). SIMULINK models can be simulated from the graphical simulator window, or the command-line. I find the latter more useful, because it allows, for example, parameter estimation and Monte-Carlo simulation.
SIMULINK models are saved as MATLAB files. Thus if one needs to write a general
ODE which cannot be expressed in SIMULINK, then one can (probably) write the MATLAB file directly. I think that SIMULINK files are still needed to simulate the ODE.
234
Some limitations of MATLAB 4.0 are: (1) User needs familiarity with matrices, and
engineering/applied math concepts; (2) Previous experience with language such as C/
FOrtran; (3) Sometimes simulator doesn't give proper results (sti PBPK models) Needs
careful attention to choice of algorithm/simulation parameters. (4) dicult to handle discrete events.
D. Russell Wada, Pharsight Corp, 299 California Ave, Suite 300, Palo Alto CA 94306
On Nov 1997 10:03:58
In my work I use MATLAB and SIMULINK to model the transport of radionuclides in

the body.
A current project is to calculate the exhalation rate of Rn-220 (Thoron) following an inhalation of thorium oxide. (a later task will be to calculate the radiation doses) To do this I
have implemented what I call a six stage hybrid biokinetic model. I model the kinetics of
each nuclide starting with Th-232 explicitly (thus six stages), the first 5 nuclides are modeled using the biokinetic models recommended by the ICRP while the biokinetic model
for thoron is a model described by Peterman for inert gases (thus a hybrid model). All totaled, the model contains about 350 compartments. The model is sti (transfer coecients between the compartments range over 9 orders of magnitude, the half-life of Th-232
is on the order of 10^10 years and the half life of thoron is 55 sec.).
So far as I can tell, the MATLAB/Simulink combination is working well. MATLAB allows the user to choose which dierential equation solver to use both sti and nonsti
solvers. In my opinion, MATLAB is very powerful and is capable of doing just about anything you want it to.
For simple pharmacokinetic systems, you would not need to use Simulink but then you
would need to write your own MATLAB routines that describe the dierential equations
and the jacobian (Simulink does that for you). The nice thing about Simulink is that it provides a nice graphical tool to build compartmental systems such as you find in pharmacokinetics. You can "build" a single compartment and then replicate the compartment and
connect the compartments using a line drawing tool.
235
If you use MATLAB and don't want to write your own routines for optimization, probability distributions, etc. you will probably need to add various MATLAB toolboxes. So you
might want to get Matlab, Simulink, the optimization tool box, the statistics toolbox, and
perhaps, the splines toolbox. All of which add to the cost. The learning curve for MATLAB and Simulink is steep, and in my opinion the manuals that come with MATLAB are
not as helpful as they might be.
Richard Traub
PNNL
On 1 Dec 1997 at 08:42:14
Unfortunately I have not used METLAB but I have been using a similar program called
MathCad for the same purpose as you describe. I have not seen these types of programs
used in pharmacokinetics and feel there is a large potential for their use. I have used MathCad to solve dierential equations resulting from compartment model. Included are functions to solve sti equation, Fourier transform, nonlinear regression analysis, convolution
and deconvolution, Symbolic solver for example: Laplace transform, integration and dierential equations, all of which I've applied to pharmacokinetic problems. I am really happy
to see others are applying programs like METLAB and MathCad to the field of pharmacokinetics.
Barry Koplowitz
Bristol-Myers Squibb
236
S EC T I O N 25
Exponential Fitting versus Compartmental

Modeling
On 9 Oct 1997 at 10:40:16
In the course of a PK discussion recently, a colleague without much formal PK background or training asked me to explain the functional/practical dierence between compartmental modeling of, say, a data set exhibiting bi-exponential disposition, and simply fitting a bi-exponential function to the data. For some reason, I've had a hard time formulating a cogent response to this question. I'd appreciate any input and discussion on this issue, especially relating to the dierence in the recovered "parameters" (either their numerical values or their real meaning) from both methods, and the general utility of both methods. Thanks - I look forward to your input.
Keith Ward
Investigator, DMPK, SmithKline Beecham Pharmaceuticals, UW2720; 709 Swedeland
Road, King of Prussia, PA 19406
On 10 Oct 1997 at 14:51:02
Your question is a classic one, and one that has received a lot of attention from both theoreticians and experimentalists not only in PK/PD but also in the broader field of biological
and physiological modeling. There is an excellent textbook treatment of the question in
John Jacquez' classic, Compartmental Analysis in Biology and Medicine. I believe the
third edition of his book has just been published.
But a short version of the answer might be given as follows. If you fit your data set to a
sum of two exponentials, you will recover four parameters, the coecients and the exponents of
A e t + B e t
If the data are sucient, all four of these parameters will be well-defined and the classical
analyses of pharmacokinetics (AUC, etc.) can be performed.
237
For more complicated systems or when mechanistic questions are important, many investigators have found it useful to add compartmental modeling to their arsenal of analytic
tools. Most compartmental analysts will, in fact, begin their analysis by fitting the data to
a sum of exponentials, but their goal is to determine how many compartments will be necessary to adequately fit the data while still permitting estimation of the model's parameter
values with reasonable coecients of variation. There is a large body of published work in
this sub-discipline, which has been called Identifiability.
One of the advantages gained by including compartmental analysis in a suite of tools used
by pharmacokineticists, is the opportunity to assign biological or physiological meaning to
the rate constants or clearances that characterize the compartmental model. To the extent
that the model structure reflects the real processes taking place in the cells, the animals,
or the human subjects, the corresponding model parameters will serve to characterize the
activity of those processes at the time the data were collected. The reason this cannot be
said of the parameters, A, a, B, and b from the exponential fit is that all four of those parameters are functions of all of the biological processes. This can be shown from first principles. Occasionally, the numerical value of one of the exponents will be dominated by a
single biological process, but no R&D eort can aord to make this assumption. There are
too many circumstances, especially in more complicated systems, in which you will be simply wrong.
The opportunity to determine compartmental rate constants or clearances that characterize particular physiological processes is also the opportunity to pursue studies of mechanism and even drug interactions. These are both feasible and practical using the compartmental modeling approach.
Compartmental analysis also has the potential to eectively address major questions raised
in the development and approval process for any new drug. It is often the case that there
is much more information in the already-collected experimental data than can be extracted using classical pharmacokinetic approaches. This, of course, is of no consequence
for drugs that sail through the approval process; classical PK is all you need. But if you are
faced with going back to do more experimental/clinical work in order to answer a tough
go/no-go development question or a tough approval question, it seems obvious to me that
you should first try to answer that question using compartmental analysis of all the avail-
238
able data. The savings in time and dollars and the resulting competitive advantage could
be enormous.
12114 Gatewater Drive, Rockville, MD 20854 U.S.A.
On 10 Oct 1997 at 14:52:27
My attitude to this has always been that when a multi-exponential model adequately describes a problem it is not necessary and, in a sense it is preferable to use it rather than create an artificial compartment model. The dangers of compartmental models have been
stated in the past and have to do with non-identifiability and the tendency to give physiological meaning to the parameters of the compartmental model, particular the horrible micro rate constants.
However I have to qualify this position slightly. True physiological models are compartmental models and their parameters do have a valid physiological meaning. Also multiexponential models do not lend themselves to situations of changing physiology (eg reduced renal function) or dose dependent kinetics. For a drug which shows bi-exponential
disposition at low dose but has saturable elimination, I know of no other way of handling
this other than with a 2-compartmental model with Michaelis-Menten elimination from
one of the compartments (usually the first). One can describe a particular dose by a sum of
exponentials but this will not be predictive of other doses. Maybe someone else knows of
a non-compartmental (predictive) method of doing this.
Leon Aarons
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester,
M13 9PL, U.K.
239
S EC T I O N 26
First Dose in Man

On 6 Mar 1997 at 11:03:44
Group: What would be the best approach to select the dose for first clinicals (beyond the
classical AFDO guidelines) if the drug shows higher interspecies variability in metabolic
pathways (e.g., scaling not possible).
N. N. S
On 7 Mar 1997 at 10:00:28
I will start first dosing comfortably doing good pre clinical work with the drug and identify an animal model that best represent or come very close to human, then start a conservative dose escalation study with well defined pharmacodynamic variable to watch for and
establish a relationship with Cmax - PD response or clinical compliance. Once this relationship is established continue classical clinical studies with heavy emphasis on Therapeutic Drug monitoring. Best I could think is the following order.
1) In vitro liver microsomal work to identify possible metabolites in various species including Human. Some times we have to go beyond classical three species approach ( In one
case we investigated beyond 6 species to test the animal model and found Baboon a good
animal model close to Human)
2) Try to identify primary isoform responsible the metabolism of the drug.
3) comparative PK in three animal models that are close to human from the # 1 study.
4) These three studies give good idea in designing first time in Man study.
My impression is for this type of problematic(assuming all the troubles listed are true) -Good emphasis in Phase I studies and therapeutic drug monitoring will save lot of confusion during the large clinical studies.
Prasad N.V. Tata, Ph.D.
240
On 8 Mar 1997 at 22:41:44
In such cases the first dose may not be as important as the rate of dose escalation. The
first dose is where one starts a journey. Without the correct road map it may be impossible to find the destination.
The first dose of a new drug in humans should always be conservative and based on a good
preclinical work-up. However, one also would want to discover the maximally tolerated
dose (MTD) in a timely fashion. Although you do not know what the plasma concentrations will be, you may have useful information regarding the slope of concentration response relationships (therapeutic and toxic) from animal pharmacology studies. Once you
have discovered where you lie on the concentration axis of that curve in humans (e.g.,
after the first one or two dose levels) you will be able to rationally expedite the search for
MTD.
In addition, I would explore the in vitro metabolism in human liver preparations. That
should at least give you 'order-of-magnitude' estimates.
Jerey Wald, Ph.D.
Quintiles, Incorporated, Post Oce Box 13979, Research Triangle Park, North Carolina,
27709-3979
241
S EC T I O N 27
Grapefruit Juice - Drug Interaction Warnings

On 10 Sep 1997
Should drugs that have or are suspected of having possible clinically significant interaction
with grapefruit juice, have warnings against it in patient's inserts and/or doctor's data
sheets?
I am asking this because of the replies to my question (ANCHODD and PharmCare) regarding the existence of such warnings. As you may have seen there are warnings for terfenadine in the UK, felodipine in Australia and indinavir and saquinavir as well.
Both felodipine and terfenadine have proven interaction with grapefruit juice. On the
other hand neither indinavir nor saquinavir have been shown to interact with grapefruit
juice. Yet they both have the potential of such an interaction as they have low bioavailability and major CYP 3A4 metabolism.
What about cyclosporin and nisoldipine, both having documented interactions with grapefruit juice? Should cisapride have a warning as well?
Ofer Spiegelstein
Department of Pharmacy, The Hebrew University of Jerusalem, P.O.Box 12065, Jerusalem
91120, Israel
On 11 Sep 1997 at 09:48:19
What is the basis for this warning? Is it the acidity of the juice or something else? If it is
the acidity, there are other juices that should be mentioned > cranberry for one example.
Vahn Lewis
242
On 11 Sep 1997 at 09:48:46

Should drugs that have or are suspected of having possible clinically significant interaction with grapefruit juice, have warnings against it in patient=CCs inserts and/
or doctor=CCs data sheets?
Ideally, the answer would be yes. However, as I'm sure you're aware, most oce based physicians are not knowledgeable about food/drug interactions. Thus, this task falls onto the
pharmacist to inform the patient. It only becomes a part of the package label if the country's drug regulatory agency specifically asks for it, and that occurs, unfortunately, after
something bad has happened.
Both felodipine and terfenadine have proven interaction with grapefruit juice. On the
other hand neither indinavir nor saquinavir have been shown to interact with grapefruit juice. Yet they both have the potential of such an interaction as they have low
bioavailability and major CYP 3A4 metabolism.
In the US, these drugs' labels do not mention grapefruit juice as a interacting agent. One
could claim that the interaction with saquinavir is beneficial because the bioavailability of
saquinavir is so poor.
What about cyclosporin and nisoldipine, both having documented interactions with grapefruit juice? Should cisapride have a warning as well?
In our hospital, we have a listing of food-drug interactions that pharmacists inform the
nurses/prescribers of when they are seen when orders are written. It includes the above
drugs, except nisoldipine only because it is not on our formulary. At least an eort is made
to avoid the interaction when it is seen.
Dr. Vince Pearson
Drug Information Pharmacist, The Johns Hopkins Hospital, Baltimore, Maryland USA
On 12 Sep 1997 at 10:22:22
The interaction of several drugs with grapefruit juice is thought to be due to the presence
of a bioflavonoid in the juice (most likely naringin which is metabolized to naringenin in
man) and inibition of in vivo cytochrome P450 mediated drug oxidation, and is not related
to the juices acidity. However the exact nature of the interaction has not, to my knowledge, been unequivocally demonstrated. Naringin is the major bioflavonoid in grapefruit
juice (in fact this is what gives the juice its bitter taste), but is not found in many other
juices such as orange juice. There are many compounds for which an interaction with
grapefruit juice has been demonstrated (several 1,4 dihydropyridines including nifedipine,
243
felodipine, nisoldipine, and other drugs such as caeine, coumarin, terfenadine, midazolam, cyclosporine, and 17 beta-estradiol come to mind). One important point about the nature of these interactions is the rather large inter-individual variability with respect to observed increases in drug bioavailability and also the dierences observed in the magnitude
of the grapefruit juice eect for dierent drugs. Hence, in my opinion the magnitude (and
variability) of the interaction should be evaluated for each specific compound to determine if label warnings should be added to package inserts or data sheets.
John S. Grundy
On 11 Sep 1997 13:57:17
Grapefruit juice known to inhibit the metabolism of drugs that are metabolized CYP-450
3A4 isozyme. Very popular example is Terfenadine-Grapefruit interaction quoted in media
as is your cough medicine (Terfenadine) and your breakfast do not see eye to eye? something like this. Grapefruit known to ihibit the metabolism of cyclosporine.
The rationale for this type of drug interaction is believed to be Syringinine a constituent
of grapefruit juice? But there is no conclusive proof Syringinine alone is responsible for
this interaction. Hope this clarifies.
Prasad Tata, Ph.D.
Division of Bioanalytical & Drug Metabolism, Otsuka America Pharmaceutical, Inc.,
2440 Research Blvd., Rockville. 20850
On 12 Sep 1997 09:01:56
For more details on grapefruit juice interactions see:

Ameer B, Weintraub RA. Drug interactions with grapefruit juice. Clinical Pharmacokinetics
1997 August; 33 (2): 103-121
The predominant mechanism for enhanced bioavailability is presumably the
inhibition of oxidative drug metabolism in the small intestine. The
consistent findings across studies of diverse cytochrome P450 (CYP) 3A
substrates support the mechanistic hypothesis that 1 or more grapefruit
juice components inhibit CYP3A enzymes in the gastrointestinal tract.
244
From abstract of the above article.

Jane Duy
Publication Manager, Clinical Pharmacokinetics, Adis International, New Zealand
On 11 Sep 1997 14:28:58
From what I understand, grapefruit juice (I don't know if a specific chemical has been isolated) has been shown to inhibit the CYP1A2 enzyme system. The acidity has nothing to
do with these warnings. Does anybody know the clinical significance of grapefruit juice interactions? How much grapefruit juice needs to be ingested to see this? How long does
the interaction last, etc.? Any other drugs to be worried about?
Bill Murray Pharm.D.
Children's Hospital San Diego
On 12 Sep 1997 08:06:13

What is the basis for this warning? Is it the acidity of the juice or something else?
If it is the acidity, there are other juices that should be mentioned > cranberry for
one example.
Please see the commentary in Clinical Pharmacology and Therapeutics Vol 61, 4:395:400 1997.
This article by David J Spence discusses in depth interactions with grapefruit juice.
It is nothing to do with the acidity of the juice. Grapefruit juice contains naringenin
which is the aglycone of naringen, a bioflavinoid. Naringenin would appear to be in
higher concentrations in grapefruit than other citrus species, however this does need further investigation. It is known that naringenin is a 3A4 inhibitor. It has also been suggested that there may be a chemical in grapefruit which inhibits 1A2.
The inhibiting eect of grapefruit juice is remarkable, with increases in AUC with drugs
metabolised by 3A4 pathway ranging from 2 to 10 fold This is particularly important for
drugs such as terfenadine (causing QT prolongation), cyclosporin , calcium channel blockers, cisapride, HMGCoA reductase inhibitors, and midazolam.
Carl Kirkpatrick
245
Department of Clinical Pharmacology, Christchurch, New Zealand
On 12 Sep 1997 11:35:33
Grapefruit juice is known to inhibit the CYP3A4 metabolism in small bowel enterocyes
but not in the liver or colon. This inhibition is primarily due to naringen, naringenin and
6',7'-dihydroxybergamottin and possibly other constituents contained in the juice. Even
one drink or one grapefruit within hours of ingestion may significantly increase the Cmax
(up to 700%) of drugs metabolized by CYP3A4 (e.g., terfenadine, nisoldipine, cyclosphorine) and such increases may be of clinical significance. Orange juice does not appear to possess such activity.
Lown K.S. et al., J. Clin. Invest. 99:2545-2553, 1997
Benton R.E. et al., Clin. Pharmacol. Ther. 59:383-388, 1995
Bailey D.G. et al., Clin. Pharmacol. Ther. 60:25-33, 1996
Edwards D.J. et al., Drug Metab. Dispos. 24:1287-1290, 1996
Sun Dong Yoo
On 12 Sep 1997 15:13:26

What is the basis for this warning? Is it the acidity of the juice or something else?
If it is the acidity, there are other juices that should be mentioned > cranberry for
one example.
Grapefruit juice (the only citrus fruit juice) has an enzyme inhibitory eect. It is discussed
that some of the flavonoid glycosides (narigin or the aglycon naringenine) which are partly
responsible for the bitter taste of grapefruit juice, are the active compounds. There are several in vitro results, that there is an Cytochrome P450 IIIA4 inhibiting eect with these
flavonoids, but in vivo studies with the pure flavonoid are sparse and without a clear outcome. Additionally there are some more compounds wich occur in grapefruit juice and not
in orange juice (wich does not act as an enzyme inhibitor). These compounds (coumarins
and psoralens) also showed enzyme inhibitory properties. As far as I know there is nobody,
who really knows what compound it is, which inhibits the metabolism of drugs metabolized by Cyt. P450 IIIA4.
246
Ralph Quadflieg, Pharm D

Department of Pharmaceutical Technology and Biopharmacy, Universtity of Bonn, An der
Immenburg 4, D-53121 Bonn, Germany
On 15 Sep 1997 at 10:59:02
I want to add a new twist to the current knowledge on the inhibition of P450 3A4 isozyme
by constituents present in the grapefruit juice.
There is convincing data in the literature that grapefruit juice constituents inhibit P450
3A4 metabolism in the gut but not liver. This findings provide a simple and practical
method of distinguishing gut versus hepatic first-pass metabolism of highly cleared drugs.
All one would have to do is to assess the degree of first-pass metabolism produced by pretreatment with ketoconazole (potent inhibitor of 3A4 in the liver and gut) and grapefruit
juice. The dierence in clearances between these two treatments could then be utilized in
calculating the contribution of first-pass metabolism by gut. Optimal conditions for such a
study would naturally would have to be worked out. There is no simple method currently
to distinguish between gut versus hepatic first-pass metabolism without the use of intravenous administration.
I would be most grateful for any comments and suggestions on my above hypothesis.
Aziz Karim, Ph.D.
Chicago, Illinois, USA
On 15 Sep 1997 at 15:23:45
I disagree with the experimental method proposed by Dr. Karim for determination of the
contribution of the gut to the bioavailability of compounds metabolized by CYP3A4. Ketoconazole would also alter the systemic clearance of the compound you want to evaluate;
hence, comparison of oral clearances of a compound given with grapefruit juice or ketoconazole would give inaccurate results for the contribution of the gut to the bioavailability
of a compound (i.e., when comparing bioavailability, relative bioavailability calculations,
one assumes that systemic clearance remains constant). However, based on somewhat
similar reasoning a simpler experiment can be done. Just compare the relative oral bioavail247
ability of your compound adminstered without and with grapefruit juice (assuming that
grapefruit juice does not aect systemic clearance; this has been shown with compounds
such as cyclosporine and midazolam). This is analagous to the ratio of F(without grapefruit juice) to F(with grapefruit juice) which gives Fg (i.e., F=Fg*Fh; where F is oral bioavailability and Fg and Fh are the fractions of the dose escaping destruction in the gut and
liver, respectively).
John S. Grundy, Ph.D.
On 15 Sep 1997 22:03:02
I am intrigued by Dr Karim's thinkings on grapefruit inhibiting only gut 3A metabolism.

This is certainly a departure from current ideas. Could someone please provide a citation?
I also wonder if anyone has given thought to grapefruit's contribution to p-glycoprotein
(MDR1) inhibition? If indeed, as thought, PGP works in concert with 3A gut metabolism
it makes sense to me that there may be some inhibitors that eect either both or just one
of the two systems. By the same token, it also makes sense that there could well be some
agents which are substrates for only one of the two systems (i.e., PGP but not 3A).
Certain enigmatic drug interactions occur which are not predicted by current, state of the
art, in vitro prediction models. As an example of this, I invite everyone to look at the
drug interaction section of the label from HMR's fexofenadine HCl. I know of no data
available in the literature to explain these findings, and oer no speculation. I just think
that it is things like this that demonstrate weaknesses in our current mechanistic paradigm
of drug interactions.
On 16 Sep 97 03:58:15
I appreciate the comments made by Dr Grundy. His comments still do not contradict the
interesting possibility that grapefruit juice can be used (even without ketoconazole) for determining the extent of gut first-pass metabolism.
In my suggested design, grapefruit juice and ketoconazole would not have been given together but in a crossover fashion after a suitable washout period. This would bring the
clearance of the test drug back to the control level similar to what we do in a comparative
248
crossover bioavailability studies. This of course assumes that the inhibitory activity of
both ketoconazole and grapefruit juice are reversible (not an unreasonable assumption)
Aziz Karim, Ph.D.
On 16 Sep 1997 04:17:36
Dr. Karim:
There are several well described experimental approaches to studying the oral bioavailability of drugs. To accurately assess the contribution of individual components such as the
fraction of absorbed dose, gut and liver extraction is no simple task. There is a series of excellent articles published recently by Seattle group (Thummel) on midazolam and Benet's
work with cyclosporin. In my opinion, these articles are particularly valuable since the assessments were conducted in humans. If more physiological and direct approach is
desired, animal models are the only alternative. The group at the University of Alberta (led
by Y.K. Tam) has published a series of papers, describing instrumented conscious dog
model that provides a very powerful tool to evaluate the first-pass eects in a great detail.
I hope this helps and provides some guidance for your experimental design.
Andrej Skerjanec, Ph.D.
Lilly Laboratories for Clinical Research
On 19 Sep 1997 at 10:42:04
There are 6 examples of grapefruit juice interaction noted in the current PDR:
PLENDIL (felodipine) The bioavailability of PLENDIL is not influenced by the presence
of food in the gastrointestinal tract. In a study of six patients, the bioavailability of felodipine was increased more than two-fold when taken with doubly concentrated grapefruit
juice, compared to when taken with water or orange juice. A similar finding has been seen
with some other dihydropyridine calcium antagonists, but to a lesser extent than that seen
with felodipine.
NEROAL Capsules (cyclosporine) Patients should be given careful dosage instructions.
Neoral(R) Oral Solution (cyclosporine) oral solution for micro-emulsion) should be di249
luted, preferably with orange or apple juice that is at room temperature. Grapefruit and
grapefruit juice aect metabolism of cyclosporine and should be avoided.
SULAR (nisoldipine) Nisoldipine should not be administered with grapefruit juice as this
has been shown, in a study of 12 subjects, to interfere with nisoldipine metabolism, resulting in a mean increase in Cmax of about 3-fold (ranging up to about 7-fold) and AUC of almost 2-fold (ranging up to about 5-fold). A similar phenomenon has been seen with several
other dihydropyridine calcium channel blockers.
CRIXIVAN Capsules (indinavir) Administration of a single 400-mg dose of indinavir with
8 oz. of grapefruit juice resulted in a DECREASE in indinavir AUC (26% +/- 18%). Administration of a single 400-mg dose of indinavir with 200 mg of quinidine sulfate resulted in
a 10% +/- 26% increase in indinavir AUC.
XANAX (alprazolam) Available data from clinical studies of benzodiazepines other than
alprazolam suggest a possible drug interaction with alprazolam for the following: diltiazem, isoniazid, macrolide antibiotics such as erythromycin and clarithromycin, and grapefruit juice.
LEXXEL (felodipine) As with other dihydropyridine calcium channel blockers, the bioavailability of felodipine was increased when taken with grapefruit juice, compared to when
taken with water or orange juice.
Norman Schmu
On 23 Sep 1997 at 10:48:56
In reference to the above subject. I would like to add

Drug Interactions with Grapefruit Juice Barbara Ameer and Randy A. Weintraub Clin.
Pharmacokinet. 1997 33, 103-121.
This seems to be a useful review. Another article I stumbled was
The fate of Naringinin in humans: a key to grapefruit juice-drug interactions Fuhr U and
Kummert, A. Clin Pharmacol. Ther. 1995, 58: 365-73.
Prasad Tata
250
S EC T I O N 28
Help with Unusual PK Problem

On 20 Oct 1997 at 12:34:01
I have the following drug pk problem to analyze:

Procedure: Drug administration: single IV bolus injection to dog, Drug dose: 1 mg/kg
Results
251
Time (hr)
Conc (g/mL)
0.25
2.13
0.5
1.81
1.94
1.5
1.87
2.21
2.17
2.66
2.46
1.89
10
1.53
12
0.9
18
0.22
24
0.8
Questions:
1. How can the data be analyzed? Can this data be modeled on WinNonlin? What model
should I use?
2. What does this data mean? The blood concentration of the drug remains the same or
slightly rises over the first 4 hours following IV bolus injection to the dogs, then falls rapidly. We have dosed two other dogs with the same results. This seems unusual to me. Is
there another example of a drug that behaves in this manner?
Tom Wallace
[Without looking at the graph - could it be enterohepatic recycling - any meals/food provided - what is the assay variability - db]
252
On 20 Oct 1997 14:43:17
I would pursue enterohepatic recirculation. You may want to perform the initial study in
rats before choosing to attempt the same more time consuming and expensive procedure
in dogs. Cannulated rats can be purchased from several sources.
Steven J. Weber
On 20 Oct 1997 13:57:24
I realize this doesn't respond directly to your question, but what are the SD's of your serum level data, so that each level can be given its proper credibility in whatever fitting
process is done? It also looks as though you will have to evaluate several dierent compartmental models before you get an idea which model is best.
90033
http://www.usc.edu/hsc/lab_apk/
On 20 Oct 1997 18:27:19
Tom Wallace posted a PK data set with somewhat unusual characteristics and asked for
possible interpretations. Among metabolic systems there are several that display kinetics
such as Tom describes. One with which I have a lot of personal experience is the plasma
lipoprotein delipidation cascade. This consists of a series of metabolic conversions (catalyzed by a pair of plasma lipases) that converts very low density lipoprotein (VLDL) to
IDL and then to the notorious LDL, which finally is cleared from the circulation by the
famous apoB receptor. In the early days of this field, VLDL and IDL were isolated together and their combined kinetics looked a lot like Tom's drug concentration time
course. (a small peak or even a frank plateau followed by an apparently exponential decline.
In Tom's case, a lot depends on whether you believe the point at 18 hours or the point at
24 hours. If both are correct the system is even more complex and David's suggestion of
enterohepatic recycling could be invoked. But I'd be inclined to believe the 18 hour point
253
and to use a model consisting of a series of compartments with elimination from the last
of them. You would fit the data against the sum of all the compartments, and the injection
would be into the first compartment. I have no doubt that the data set Tom supplied
could be fitted to such a model.
Then the question becomes what is the physiological significance of this cascade? Without
knowing more about the compound Tom administered, it's hard to say for sure, but a good
initial hypothesis would be that the drug is processed intravascularly and only after several
steps does it become a substrate for its clearance mechanism. To evaluate this you'd first
want to know for sure that your assay measures only the parent compound and not its
metabolic successors. A second hypothesis perhaps worth testing, is that the compound
has a high anity for VLDL and is adsorbed onto the surface or even dissolved in the core
lipid of this lipoprotein. This would result in kinetics that are determined by lipoprotein
processing, and in eect the drug becomes a tracer for lipoprotein metabolism. Under
some circumstances, this could be a gold mine.
The bottom line is that a likely model for the data set Tom posted is a series cascade with
the data fitted to the sum of all the compartments and elimination from the last. Models
like this are easy to build and fit to data using compartmental analysis packages like
SAAM 31, SAAM II and ACSL BioMed to name just the ones I'm at least a little familiar
with. There are many others, for example ScoP, and it may even be that WinNonlin will do
this problem. The software is not the key. The key is recognizing the nature of the problem, and my best shot at doing that is the cascade mechanism described above.
Tom, there are definitely solutions to this class of problems. Let me know if I can be of further help.
BioInformatics Services, 12114 Gatewater Drive, Rockville, MD 20854 U.S.A.
On 20 Oct 1997 20:14:44
Sorry, cannot comment on equations, but, could this be an example of redistribution from
another compartment? Another example might be diazepam diusion from blood to CNS
254
and then diusion back from CNS to blood. (Reason why lorazepam is recommended over
diazepam for treatment of seizures.
Greg Soon
Pharmacist - ICU/Surgery, Peterborough Civic Hospital, Peterborough, ON, Canada
On 21 Oct 1997 16:29:47
We analyzed your data using the CXT software package. Since we did not know the
weight of the dog, we estimated it as 15 kg, so we used the total dose of 15000 micrograms. Below please find the model function describing behavior of your system:
C(t) = 15000*2.51E-3*{0.0459*exp(-0.0572*t)+0.0859*exp(-0.5708*t)+
-0.0558*exp(-167.6102*t)+
exp(-0.1551*t)*[-0.0738*cos(0.3372*t)+0.052*sin(0.3372*t)]+
exp(-0.0102*t)*[-2.1112E-3*cos(0.5939*t)+2.0337E-3*sin(0.5939*t)]}
You can plot this model function and compare it with the data measured. The value of the
Akaike criterion is: 10.4. On the basis of this preliminary model, it is possible to estimate pharmacokinetic parameters e.g.:
Clearance=(1/2.51E-3)=398.4 mL/h
AUC=37.65 microgram*h/mL,
MRT =14.9h
AUC_residual.28%.
This model function is a solution of the seventh-order dierential equation, indicating a time delay in your pharmacokinetic system. It follows then that, your system
cannot be described by a multi-exponential model. We would recommend you to add
the following sampling points: 5, 10 min., 15, 21, 27, and 30 h.
Maria Durisova and Ladislav Dedik
255
On 21 Oct 97 16:39:59
Interesting problem...
Procedure: Drug administration: single IV bolus injection to dog Drug dose: 1 mg/kg
This raises further questions:

1.
What was the drug? (I seem not to be able to find it in your note.)
2. What was the salt of the drug?

3.
Was it inadvertantly administered SC or intradermally?
4. How was it administered IV (?via a cannula or other tubing, was the tubing flushed?)
5.
How were the blood samples taken (via the same cannula?, how much blood was discarded from the sample before the remainder was kept for assay...?)
6. What condition was the dog in? (any relevant pathology?)

Steve Duull
On 21 Oct 1997 12:46:15
What is your detection limit? The noisy data may due to the concentration closed to or
below the detection limit.
Jian-hua Liu
On 22 Oct 1997 21:39:48
Problem: sustained concentrations following iv bolus administration

You don't mention any of the drug characteristics, particularly its solubility.
When I was injecting Tribrissen, a suspension of Trimethoprim and solution of sulfadiazine, into 1 day old calves we found that Trimethoprim (TMP) seemed to adhere to the
walls of the vein (jugular) and give us a prolonged "distribution phase". It was not as dramatic as the data presented here but it may be the same phenomenon. Also, are you sampling from the same vein as you injected from? This can really "inflate" your plasma values.
Susan E. Shoaf
256
On 24 Oct 1997 at 09:39:27
About detection limits. This is an interesting issue. It relates in general to the problem of
assigning the correct weight to a serum level (or any other) data point when fitting it by almost any method, and in optimal population modeling.
The really important thing is to KNOW the error with whith each serum level is measured. Often people choose weighting by the reciprocal of the concentration, or its square.
The best, I think, is to know the standard deviation (SD) with which each and every serum level is measured. Then one can correctly weight each level by its Fisher information,
the reciprocal of its variance, in the modeling process.
Unfortunately, most labs have not done this. Once the error, usually the coecient of variation, has been shown to be within socially aceptable limits, then the actual errors are too
often ignored, and not realistically incorporated into the fitting process.
We suggest that one determine, empirically, in at least quadruplicate, the SD of representative concentrations over the working range of the assay - for example, of a blank, a low, a
medium, a high, and a very high level. Now, fit the relationship of SD to concentration
with a polynomial to capture this usually nonlinear, convex upward, relationship, so that
you can estimate the SD from the serum concenreation that is measured. Having done
this, one now has a pretty good, and cost-eective way to get an estimate of the SD with
which any single level is measured.
These issues are discussed in more detail in
Jellie R: Explicit Determination of Laboratory Assay Error Patterns - A Useful Aid in
Therapeutic Drug Monitoring. The Americal Society of Clinical Pathologists CHECK
SAMPLE continuing education program, Drug Monitoring and Toxicology, 10: No. DM 89-4
(DM-56), 1990, and Jellie R, Schumitzky A, Van Guilder M et al: Individualizing Drug
Dosage Regimens: Roles of Population Pharmacokinetic and Dynamic Models, Bayesian
Fitting, and Adaptive Control. Ther. Drug Monit. 15; 380-393, 1993.
The point of this is that for toxicology, one MUST have lower detectable limits, as there is
no other way tomake a decision as to whether the drug is present or not. However, for
TDM or for PK studies, one usually knows quite well how long after each dose the semple
was measured, and we also know that for most linear systems, at least, one never gets rid
of the last molecule, so to speak. We therefore have the answer as to whether the drug is
257
actually there or not - it clearly IS. The only question remaining is what concentration,
and with what error.
It has been common to think that when the levels get very low that the coecient of variation approaches infinity. True enough, but what about the SD and the variance, and therefore, the Fisher information? All this is knowable right down through low levels, all the
way down to the blank. Because of this, there is actually NO LOWER DETECTION
LIMIT for samples measured when the time after the last dose is known, at least for drugs
having linear models. Using such polynomials, fron which the SD of each level can be estimated usually easily and quite well, the correct weight appropriate to its credibility can be
given. For TDM at least, this whole question of lower detection limits has been a cultural
problem derived from toxicology, not from TDM. Look at the articles and let me kow
what you guys think, and let's continue to talk about it.
90033
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S EC T I O N 29
High/Low Extraction Drug

On 25 Apr 1997 at 12:12:38
Does anyone have any information on how to predict whether or not a drug is high or low
extraction ?
I am trying to determine what the consequences of a decrease in hepatic perfusion (CHF)
will have on a drug that is eliminated almost entirely via hepatic metabolism.
Christopher Houle
On 28 Apr 1997 at 11:20:11
I think a high partition coecient is a hint that a drug will be a high extraction drug. e.g.
Propranolol, lidocaine etc.
Steven Pomarico
On 28 Apr 1997 at 11:22:21
There are 2 papers which might help you. They show the usefulness of hepatocytes or liver
microsomes (rat and human) to classify compounds into Low/Int/High hepatic extraction
ratio, based on their in vitro metabolic stability :
J. B. Houston, Biochem. Pharmacol. 47, 1469-1479, 1994
Th. Lave et al., Pharm. Res., 14, 152-155, 1997
Thierry Lave
259
S EC T I O N 30
High Throughput Pharmacokinetics

On 10 Sep 1997 at 10:47:38
In order to increase screening eciency early in drug discovery, using a cocktail dosing solutions containing a certain number of drug molecules (~5) seems to be an attractive approach for PK studies. Drug interaction seems one of the major concerns. How one can
minimize drug interaction and obtain reasonably useful information from cocktail design?
Are there some studies published?
What kind of criteria should be employed in selection of drugs which are going to be formulated as a cocktail dosing solution? Analog series vs. heterogeneous group of molecules
Majid Vakily Ph.D.
Principal Research Scientist, Homann La Roche, Drug Metabolism and
Pharmacokinetics/Discovery, Room No 1545
On 11 Sep 1997 at 09:47:20
There is only one study that I am aware of: Berman et al., J. Medicinal Chem., 40; 827-829
(1997).
Michael Mayersohn
On 11 Sep 1997 at 09:47:53
You might be interested in the following two papers:

Berman, J. et al. 1997 Simultaneous pharmacokinetic screening of a mixture of compounds
in the dog using API LC/MS/MS analysis for increased throughput. J. Med. Chem. 40: 827829.
260
Olah, T.V. et al. 1997 The simultaneous determination of mixtures of drug candidates by
liquid chromatography atmospheric pressure chemical ionization mass spectrometry as an
in vivo drug screening procedure. Rapid Commun. Mass Spectrom. 11:17-23.
DR P.H. Van der Graaf
Leiden/Amsterdam Center for Drug Research, Department of Pharmacology, P.O. Box
9503, 2300RA LEIDEN The Netherlands
261
S EC T I O N 31
History of Pharmacokinetics
On 3 Sep 1997 at 10:15:37
I am preparing a set of lessons about clinical PK, and I wish to introduce it by an historical perspective. However, textbooks and review papers contain few references on that
topic. Would someone know about seminal works and papers on PK in the past ? Who introduced first the concepts of compartment models to describe the fate of drugs in the
body ? When was the relevance of such descriptions recognized as clinically important ?
Which were the most cited papers in that field some decades ago ?
Thierry BUCLIN, MD
Division of Clinical Pharmacology, University Hospital CHUV - Beaumont 633, 1011 Lausanne - SWITZERLAND
On 4 Sep 1997 at 10:20:17
This seemed to be a popular question ;-) so I've put the replies received this morning together in one message. It seems John Wagner's paper and book are good reviews with the
Rescigno and Segre book another early reference.
From Gibaldi and Perrier's first edition of Pharmacokinetics some early names include
Dost, Kruger-Thiemer, Nelson, Teorell. The earliest reference listed was by Teorell. See
the reply by Schoenwald below for the citations.
Wagner's book Biopharmaceutics and Relevant Pharmacokinetics provides a biography starting on page 331 (as mentioned by Schoenwald and lists as the earliest paper;
Hanzlik, P.J.: The absorption of sodium iodide, J. Pharmacol. Exptl. Therap. 3:387-421, 1912
David Bourne
262
On 3 Sep 1997 12:16:05
A paper by John Wagner History of Pharmacokinetics, Pharm. Ther. Vol. 12. pp 537 - 562,
1981 contains good historical information on the subject.
Don Gibson
Parke-Davis
On 3 Sep 1997 12:54:50
In the late 1960s, when I first learned about kinetics, the seminal book was by Aldo
Rescigno and Giorgio Segre. It's title is Drug and Tracer Kinetics published by Blaisdell 1966, based on a translation of the Italian edition published in 1961. Since that time
numerical solutions of the full dierential equation systems have largely supplanted the
Laplace transform methods of this book, but no review of the history of PK could be complete without reference to Rescigno and Segre.
On 3 Sep 1997 13:13:51
In Pharmaceutical News there were series of articles by Dr. Gibaldi they should help you.
Vol 1 of Phamacokinetics and Biopharmaceutics presented a historical perspective.
Food thought who could have started the idea of Pharmacokinetics
My thought is Anesthesiologist.
Prasad Tata
On 3 Sep 1997 13:23:35
The best "History of Pharmacokinetics" review of which I'm aware was written by John
Wagner. The reference is as follows:
263
Wagner JG. History of Pharmacokinetics in International Encyclopedia of Pharmacology and Therapeutics, Section 122. Pharmacokinetics: Theory and Methodology. Rowland M and Tucker G. (eds). Pergamon Press, NY, 1986.
Jim Coyle, Pharm.D.
College of Pharmacy, The Ohio State University, Columbus, OH
On 03 Sep 1997 18:45:02
An excellent bibliography of early pharmacokinetic work is referenced in Chapter 43 of

Wagner's text titled, Biopharmaceutics and Relevant Pharmacokinetics 1st edition,
Drug Intelligence, 1971. Page 331 of this text lists two papers by Torsten Teorell that I
have always assumed to be the first publication of a solution to a two compartment open
model along with the assumptions important to the modern definition of multicompartments. The reference is Arch. Intern. Pharmacodyn., 57:205-225, 1937 and ibid, 57:226-240,
1937. The bibliography is excellent with regard to papers published prior to 1963.
Ron Schoenwald
Professor, Pharmaceutics Division
On 04 Sep 1997 08:09:08
I would recommend an old review by Prof. Wagner:

Wagner JG. 1981 History of pharmacokinetics. [Review] [269 refs] Pharmacology & Therapeutics. 12(3):537-62
Vladimir Piotrovsky
On 4 Sep 1997 08:29:36 +0200
Dr. John Wagner wrote an excellent paper about 'History of pharmacokinetics' which appeared in Pharmacology and Therapeutics in the beginning of the 80s and in International
encyclopedia of Pharmacology and Therapeutics Section 122 (Ed. m.Rowland and
G. Tucker), 1986, Pergamon Press.
264
That paper contains many of the early references you may be looking for.
Other good references on the early work are by Rescigno and Segre, 'Drug and Tracer kinetics', 1961, 1966, Blaisdell Publishing Company or D.S. Riggs 'Mathematical Problems to
physiological problems, 1963 Williams and Wilkins, or by Lassen and Perl 'Tracer Kinetics
Methods in Physiology', 1979, Raven Press.
Johan Gabrielsson
On 3 Sep 1997 20:47:17
There is a PK history paper a few years ago by John Wagner of Upjohn. You might find
this of value.
Xiaofeng Wang
On 5 Sep 1997 at 10:52:07
I have information probably of interes for you in the topic of history of PK:
Pharmacokinetics Bibliography. Revision of Prof. Edward Garret in the Course of Pharmacokinetics (Gainesville, Florida). I have the edition of 1981. This revision is a expanded
from:
A Bibliography of Selected Pharmacokinetic Topics by David H. Coccheto and Willian A.
Wargin, Drug Inte!igence and Clinical Pharmacy, 14, 769 (1980).
Spanish publications of this topic:
a) Evolucion historica de la Biofarmacia y farmacocinetica, una nueva disciplina farmaceutica. I.G. Alonso, J.M. Lanao, A. Dominguez-Gil. Industria Farmaceutica: 2: 151-156. 1990.
b) Biofarmacia y farmacocinetica: aproximacion historica. I. Origenes y ecuador de la farmacocinetica. Lopez Guzman, J., Vidal Casero, M.C., Pla Delfina, JM.. Ciencia Pharmaceutica. 2 (5): 349-357. 1992.
c) Biofarmacia y farmacocinetica: aproximacion historica. II. La expansion de la farmacocinetica. Lopez Guzman, J., Vidal Casero M, Pla Delfina, JM. Ciencia Pharmaceutica. 2(6):
419-432. 1992.
265
c) Biofarmacia y farmacocinetica: aproximacion historica. III. Biofarmacia: estudios de biodisponibilidad. 3(1): 41-54. 1993.
d) Biofarmacia y famacocinetica: aproximacion historica. IV. Biofarmacia: modulacion de la
biodisponibilidad. 3(2): 97-116. 1993.
e) Farmacia Clinica, farmacocinetica y adminstracion de medicamentos. Marino, E.L., Modamio, P., Montejo, O., Lastra, C.F. Rev. O.F.I.L. 6 (4): 258-270. 1996.
- The exactly information about the book of Rescigno and Segre, is:
DRUG AND TRACER KINETICS, ALDO RESCIGNO. University of New South
Wales, Australian National University., GIORGIO SEGRE. University of Camerino, Italy.,
BLAISDELL PUBLISHING COMPANY. A Division of Ginn and Company. 1966. Walthman. Massachusetts. Toronto. London.
Translated from the italian: LA CINETICA DEI FARMACI E DEI TRACCIANTI
RADIOATTIVI (1961), by PIERO ARIOTI.
In all case, I think that no review of the history of PK coul be complete without reference
to Prof. Edward Garret.
Prof. Eduardo L. Marino. Pharm. D., Ph.D.
Clinical Pharmacy and Pharmacoterapy Unit., Faculty of Pharmacy. University of Barcelona., Avda. Joan XXIII s/n. 08028-Barcelona. (Spain).
On 8 Sep 1997 at 10:19:33
In the history of pharmacokinetics, as far as I know, it begins with the work of Torsten
Theorell in 1937, who described the basic dierential equations for a 3 compartment linear
system. Then, interestingly enough, we can go back a bit further to Dr. Harry Gold at Cornell, who was the one who invented the ides of a loading dose of digitoxin followed by a
maintenance dose. About 1929, for example, ie talks about cumulation being a self-limited
phenomenon, and about each patient eliminating a certain fraction of drug from his body
each day. In JAMA 92: 1421-1423, 1929, you see this. In later works you can see that he has
not followed this through formally, and, without any assays, gets this idea confused with an-
266
other one, that it may require more digitalis to get a patient out of failure than to keep
him out of failure after that.There are articles about 1932-33 that show this.
Then we can jump to the work of A. Augsberger in Klinische Wochenschri% 99; 945-951,
1954, Quantitatives zur Therapie mit Herzglycosiden, who took the ratios of comminly accepted ratios of loading and maintenance dosed of verious digitalis compounds, worked
out their kinetics from this, and compared these predicted amounts of digitoxin, for example, with the eect of it on ventricular rate in A fib as studied by Gold later on in 1946. He
also showed examples with Cedilanid and Acetyl digoxin. To my knowledge, this was the
first truly pharmacokinetically oriented work dealing with digitalis therapy in its quantitative and pharmacokinetic aspects.
Then came Ekkehard Kruger-Thiemer, who laid out the formal theory of drug dosage regimens is several good articles in J Theoret Biol in 1966. Our work on digitalis built on this,
and was first described in Math Biosciences 1: 305-3325, 1967, Ann. Int. Med. 69: 703-717, 1968,
and 72; 453-464, 1970, and Math Biosciences 14: 17-24, 1972.
90033
On 19 Sep 1997 at 10:27:37
I may have missed some part of the email exchanges related to the history of pharmacokinetics. Accordingly, I may duplicate information you already have.
I believe that one important person in this context is F.H. DOST from Germany who published in 1953 (Georg Thieme, Leipzig) the book: Der Blutspiegel: Kinetik der
Konzentrationsablaufe in der Kreislaufflussigkeit. It is said that in this book he
coined the word "Pharmakokinetik". This is a least what is written in the Foreword of the
second edition Grundagen der Pharmakokinetik of 1968 (Georg Thieme Verlag Stuttgart).
Luc P. Balant
Department of Psychiatry, 2, Chemin du Petit-Bel-Air, CH-1225 CHENE-BOURG
267
S EC T I O N 32
How are Tumor Drug Concentrations

Measured
On 28 Feb 1997 at 11:51:25
We have been trying to measure drug concentrations in tumors. The problem we run into
is the blood vessels surrounding the tumor. If we grind the tumor with the blood vessels,
we will be measuring some composite value of the concentration of drug in tumor and in
blood. We have tried to remove the blood vessels surrounding the tumor but have not
been able to do it successfully. I was wondering if anyone in this group has experience in
measuring the concentration of drug in tumors with a significant amount of vasculature. Is
there a way to remove the vasculature or correct for the contribution of drug in blood to
calculate the concentration in tumor? Any guidance you might have on this topic will be
appreciated. Please include any references that discuss this issue.
Chetan D. Lathia
Pharmacokinetics and Drug Metabolism, Parke-Davis Pharmaceutical Research
On 3 Mar 1997 at 12:15:08

was wondering if anyone in this group has experience in measuring the concentration of
drug in tumors with a significant amount of vasculature. Is there a way to remove the
vasculature or correct for the contribution of drug in blood to calculate the
concentration in tumor?
This enquiry begs the question "Why do you want to measure drug concs in tumor?". Assuming you want to know the conc at the site of action, even if you could find a way to
measure 'blood free' conc in a tumor you still do not know the conc at the site of action
but just the average conc in all the (non-blood) tissues (which depending on the tumor
could be quite variable).
This average conc is not the 'true' conc at the site of action but just represents binding
and partition among all the tissues in the sample which would only resemble the conc at
the site of action by very good luck.
268
It is my personal opinion that all attempts at so called tissue conc measurements based on
grinding up heterogeneous tissue masses are a form of fool's gold. Unless you have some
good reason to believe that there is active transport to the site of action (or active transport out of the site) then concs at the site of action will be proportional to unbound conc
in blood at steady state - so you may as well measure blood concs and forget messing
around with the tissue.
So please let us know why you think blood free tissue concs would be useful to you.
Note that you can get an approximate answer by injecting the animal with a marker substance that does not cross blood vessels, measures its conc in blood and the amount in the
tissue and thus work out the volume of blood in the tissue. If you know the blood conc of
your drug then you can figure out the amount of your drug in the blood in the tissue. Similar principles can be used to work out the amount of extra-cellular drug.
Nick Holford
On 3 Mar 1997 at 12:19:15
We use a correction factor for blood volume to account for the amount of material residing in the vasculature of that tissue. A detailed review on this can be found in the book entitled Liposome Technology, 2nd edition, Volume 3 (Interactions of liposomes with biological milieu) edited by G. Gregoriadis. See chapter 3, the article written by Marcel Bally,
Lawrence Mayer, Micheal Hope, and Rajiv Nayar, "Pharmacodynamics of liposomal drug
carriers: methodological considerations" (1993, CRC Press). Correction factors (red cell
volume and blood volumes) for tumor and non-tumor bearing animals are listed here.
Trust this is of help.
Rajesh Krishna
BC Cancer Agency, Vancouver, BC
http://members.tripod.com/~rkrishna/index.html
269
On 3 Mar 1997 at 12:22:46
The issue raised here by Dr. Lathia has quite interesting implications, and is one that we
have been concerned for many years. Originally, in the 1970's, we would express our biodistribution data in a variety of forms:
% ID [injected dose]/g of tissue, total
% ID/g of tissue, blood corrected
% ID/organ, total
% ID/organ, blood correct
% RD [retained dose]/ of tissue, total, etc, etc,
where the injected dose [ID] is the total amount of the drug administered to the animal,
and where the retained dose [RD] is the amount of the drug remaining at time t. Each of
these values may have some relevance. See for example: Synthesis and Distribution of
195mPt-cis-Dichlorodiammine Platinum (II). W. Wolf and R.C. Manaka. J. Clin. Hematol.
Oncol., 7, 79-85 (1977).
There are, however, many more issues to consider that an simple correction, and assuming
that the tumoral blood pool is totally "external" to the tumor cell mass may not be correct.
1.
Which is the specific tumor that is being studied? Not all tumors are the same. Their
growths may be significantly dierent, their microvasculature structure may have differences, as we have begun to show. See: Pharmacokinetic Imaging of Animal Tumors
can be Used to Evaluate the Pathophysiological Compartments that Regulate Drug Delivery. Alfredo R. Sancho, James A. Dowell and Walter Wolf. Abstract PPDM 8245, presented at the 1996 Meeting of the AAPS. Pharm.Res. 13:S-454, 1996.
More of this work, where we have shown how it is possible to measure, non-invasively,
the vascular space in a given tumor mass, will be presented at the upcoming AACR
meeting.
2. We have also noted that an understanding of the tumoral microvascular space may be
quite relevant to our understanding of drug transport into tumors, and this can be
graphically seen in two posters presented at the recent meeting on the Future of NMR
270
in Medicine. These posters, Magnetic Resonance Spectroscopy (MRS) allows

Pharmacokinetic Imaging (PKI) Studies in Human Tumors. Walter Wolf, Victor
Waluch, Cary A. Presant and Hyun K. Kim., and Magnetic Resonance Imaging in
Functional Studies of Human Tumors. Hyun K. Kim, Victor Waluch, Alfredo Sancho,
Cary A. Presant and Walter Wolf, both of them presented at the first Internet Conference on the Future of Magnetic Resonance in Medicine, Japan, January 27-February 3,
1997 may be viewed at our URL http://www.usc.edu/hsc/pharmacy/pkimaging/posters.html
Thus, rather than ignoring the microvascular space, we postulate that it may, together with
the tumor's interstitial space and the tumor's intracellular space, be one of the important
elements to consider in the rather complex picture of how drugs get delivered to tumor
cells. The availability of pharmacokinetic imaging methods allows the direct measurement
of such spaces in individual animals - and in humans.
On 3 Mar 1997 at 12:25:09
Not knowing the characteristics of your tumor, I'm going out on a limb as I make the following comments.
This is a classic dilemma faced by anyone who has tried to target tumors. The tumor vasculature is going to vary from tumor to tumor, how the tumors dierentiate, etc.. When I
used to work on radioimmunoconjugates, we washed the tumors as best as we could with
saline/PBS etc and then counted the tumors for radioactivity. To show specific tumor uptake we would use a control that was non-binding. This would give us an idea of blood
pool eects. Without belaboring much on this issue, here are a few suggestions: 1. If this
is a targeted agent, then the solution is easy. Use a similar molecule but without any binding specificity. I am assuming here that the targeting vector is distinct from the drug.
Otherwise, try the following: 2. If it is a small molecule then determine the concentration
of your drug in the tumor (before extensive washing), following washing. You might even
271
want to slice the tumor open, if it is a solid tumor. If you then compare the Tumor to
Blood ratios, you ought to get a feel for specific tumor concentrations. Of course, this will
only be an estimate at best
There is no easy solution to your problem, unfortunately.
Vinay Desai
Nycomed Inc.
On 4 Mar 1997 at 13:03:14
I don't have any experience in measuring drug concentrations in tumors. But we use microdialysis to measure drug concentrations in liver. People have used microdialysis in tumors also. You implant a microdialysis probe which consist of a dialysis membrane. The
probe is perfused with a solution isotonic to the tumor medium. The small molecular
weight drug will pass through the dialysis membrane and be carried away by the perfusion
fluid which can be collected and assayed. The samples are protein free so you don't need
any sample preparation or tissue grinding. Since you can place the probe anywhere in the
tumor, vasculature is not a problem. Following are some references on tumors.
1. Microdialysis Sampling in Tumor and Muscle: Study of the Diposition of 3-Amino-1,2,4Benzotriazine-1,4-DI-N-Oxide (SR 4233) R. K. Palsmeier and C. E. Lunte, Life Sciences
1994 55(10), 815-825
2. Pharmacokinetic and Metabolism Studies of 3-Amino-1,2,4- Benzotriaznine-1,4,Di-NOxide In Solid Tumors By In Vivo Microdialysis. R. K. Palsmeier and C. E. Lunte: Internat. Symp. on Microdialysis and Allied Analytical Techniques. (In: BAS' Current Separations) 1993 12:2, Abst# 55
47906
http://www.bioanalytical.com.
272
On 5 Mar 1997 at 11:39:18
Dr. Gunaratna
We had thought of using microdialysis to measure antineoplastic drug concentration in
and around tumors of various sizes that had been implanted in rats. We hesitated and did
not use this method, instead we used true noninvasive imaging methods.
My question is: How invasive is the probe? Does it perturb to a large extent the "normal"
(as normal as a tumor can be) growth and patho-histology of the tumor? Does it cause extra leakiness?
Alfredo R. Sancho,
USC-PK Imaging Ctr.
On 5 Mar 1997 at 11:41:23
Nick
I was wondering if you might suggest something for the following scenario:
I agree with you that more traditional methods of measuring drug concentration are available and up to recently used extensively. Such methods as blood sampling, urine output,
and others are considered to be the "traditional" pk drug measuring methods, from these
measurements "assumptions" through mathematical analysis and "data-processing" are
made to "estimate" or "approximate" drug concentrations in various tissues -including tumors- can be done.
My question is, when working with patients and with novel drugs or "cocktails" of antineoplastic drugs, which are highly toxic. How do you justify pushing the limits of such drugs
MTD into a patient so to sample blood and estimate the amount of drug reaching the tumor? Would it not be better to somehow administer lower dosages -less toxic, less costly,
less possibilities of negative side eects- of the same drug/s and measure non-invasively
the amount of the drug in the tumor? How else can you not perturb the system -possibly
freeing tumor cells into the bodyyet obtain meaningful data? How else can you not find
yourself making leap-of-faith assumptions from calculations?
273
You see, after studying tumors for several years, no two tumors are alike, even if they are
of the same origin and found in the same patient and tissue. Each tumor will grow in its
own radically dierent style and madness. Particularly their microvascular network. Being
that the case would you not need to measure exactly -or as precise as possible- the %ID of
your administered drug? For instance, what would happen if you make assumptions based
on blood sampling and due to the odd and unique pathophysiological factors found in tumors -e.g. microvasculature- the drug never reaches the tumor in any therapeutic amount?
And clinicians continue the protocol for several months. Would it not be nice to know if
the drug is going to reach the tumor, this from a single dose measurement? In that manner the researcher/clinician group can select the most eective drug for that patient?
Alfredo R. Sancho,
USC PK-Imaging Ctr.
On 6 Mar 1997 at 11:06:29
We've used microdialysis to measure brain extracellular drug concentrations (Scheyer,

R.D., During, M.J., Hochholzer, J.M., Spencer, D.D., Cramer, J.A. and Mattson, R.H.
Phenytoin concentrations in the human brain - an in vivo microdialysis study. Epilepsy Res.
18:227-232,1994., Scheyer, R.D., During, M.J., Spencer, D.D., Cramer, J.A. and Mattson,
R.H. Measurement of carbamazepine and carbamazepine epoxide in the human brain
using in vivo microdialysis. Neurology 44:1469-1472,1994). After several hours, microdialysis concentrations reflect the extracellular space, rather than the vascular compartment, although there may be some residual "leakiness" for longer periods.
Restoration of the integrity of tumor vascularity might be dierent, and might vary with
tumor type. Possibly of greater importance is what you wish to measure. Microdialysis is
a useful probe of the extracellular space. While this is a region of interest for many drugs,
it may not be of particular importance for antineoplastic compounds.
Dept. Neurology, Yale School of Med., P.O. Box 208018, New Haven, CT 06520-8018
USA
274
On 6 Mar 1997 at 17:51:28
Alfredo,
I agree with you that more traditional methods of measuring drug concentration are
available and up to recently used extensively. Such methods as blood sampling, urine
output, and others are considered to be the "traditional" pk drug measuring methods,
from these measurements "assumptions" through mathematical analysis and "dataprocessing" are made to "estimate" or "approximate" drug concentrations in various
tissues -including tumors- can be done.
These 'traditional' methods have been used successfully to understand how the time
course of the eects of anti-tumour agents are linked to drug dose via models of drug
concentration in plasma and at the site of action.
In the clinical pharmacology setting this has been helpful in identifying the predictable
components of the dose-eect relationship e.g. dierences in clearance from individual to
individual and from occasion to occasion within the same individual.
My question is, when working with patients and with novel drugs or "cocktails" of antineoplastic drugs, which are highly toxic. How do you justify pushing the limits of
such drugs MTD into a patient so to sample blood and estimate the amount of drug reaching the tumor? Would it not be better to somehow administer lower dosages -less
toxic, less costly, less possibilities of negative side effects- of the same drug/s
and measure non-invasively the amount of the drug in the tumor?
I did not advocate 'pushing the limits of drugs MTD...so to sample blood and estimate the
amount of drug reaching the tumor'. The kinds of studies that I am referring to may be
done during Phase I (when the MTD is determined) but have been done and have been
most informative at doses which are thought to provide optimal clinical responses. My
question about the use of so called tumor concentrations should be considered in the setting of giving the same dose to the same patient. In that case, what could be learned from
1) blood concentrations 2) invasive tumor concentrations (as proposed originally in this
thread) 3) non-invasive imaging? Which would help understand the eects of the drug? I
would think that a combination of 1) and with the others would be most informative but
the specificity of the average tumor concs or the imaging pictures as markers of concs at
the site of action would determine their relative contributory merits. Approaches which
use 1) plus some marker of drug eect and a suitable model have been very helpful (see below).
How else can you not perturb the system -possibly freeing tumor cells into the bodyyet obtain meaningful data?
A combined approach should be considered, of course.

How else can you not find yourself making leap-of-faith assumptions from calculations?
275
Most of the assumptions I need to make are based on strong biological and chemical a priori knowledge. I mentioned one such assumption in my original posting i.e. equal free
water concs in blood and at the site of action when at steady state. What leap-of-faith assumptions are you thinking of ?
You see, after studying tumors for several years, no two tumors are alike, even if
they are of the same origin and found in the same patient and tissue. Each tumor will
grow in its own radically different style and madness. Particularly their microvascular network. Being that the case would you not need to measure exactly -or as precise
as possible- the %ID of your administered drug? For instance, what would happen if
you make assumptions based on blood sampling and due to the odd and unique pathophysiological factors found in tumors -e.g. microvasculature- the drug never reaches the tumor in any therapeutic amount? And clinicians continue the protocol for several
months. Would it not be nice to know if the drug is going to reach the tumor, this
from a single dose measurement? In that manner the researcher/clinician group can select the most effective drug for that patient?
The issues of variability, from patient to patient (or tumor to tumor if you wish), are indeed very important. They have been the focus of substantial eorts among the clinical
pharmacology PKPD community. Large fractions of variability are currently without explanation so any methods that oer insights into this are very welcome. It should be noted
however that PKPD studies have been critical in understanding that the variability in drug
disposition and response from one treatment occasion to another can be so large that the
first treatment response only predicts a very small part of the second treatment. e.g.
Karlsson MO. Port RE. Ratain MJ. Sheiner LB. A population model for the leukopenic effect of etoposide. Clinical Pharmacology & Therapeutics. 57(3):325-34, 1995 Mar. reported occasion to occasion variability in EC50 was so large that the same average conc should be
targeted for all patients but the variation in clearance was small enough that use could be
made of plasma concs from the first course to predict the dose needed for the second.
An analysis based only on tumor site sampling could only have addressed the PD part (eg
very variable EC50) while a combined approach of PK and PD (using leukopenia as the effect) revealed the relative important of PK as a way to optimize response.
So please understand that I am not saying tumor concs are a waste of time. But neither do
they oer the gold standard for understanding how to use anti-cancer agents. I would still
be interested in hearing from the originator of the thread about what was hoped for by estimating blood free concentrations in a tumor.
276
It is also important to appreciate that dierent approaches are needed at dierent stages
of understanding the pharmacology of a drug. During drug discovery tumor concs may be
a very helpful screening tool for certain compounds while in phase III clinical trials blood
concs may be critical in understanding what the optimal dose might be.
Nick Holford
On 7 Mar 1997 at 09:58:19
Nick:
I am glad that the vagueness is cleared. Moreover I agree with you that a multidisciplinary method or approach is needed to truly and fully understand what happens in and
around the tumor site.
Let me throw this question in the pile:
1) If clearance is a way of calculating the amount of drug left in the blood compartment,
hence how much is left in the tumor... what model are you using to compare the tumor
compartment? There is no tissue in the body that has the same infrastructure as that of
tumors. We could not even compare it to the tissue in which the tumor is in. Therefore,
either assumptions are made or invasive measurements are needed.
Now if we agree that there is great patient inter-variability and that measurements of clearance can be used as an indicator for tumor trapping of the drug. How accurate is this? Is
is not contradictory? In the clinical scenario, would a one "common" or "average" dose
-statistically calculated from previous patients- and noninvasive measurements be in order? That is the first does measured at the tumor site itself, might be a indicator -if not a
predictor- of tumor response.
You see I put myself in the patients position... do I want to go through an entire protocol
of chemotherapy without know if it is eective or not. Based solely on "statistical analysis" of previous patient tumor response data. Or do I want to take a single dose ("average"
dose) and measure its presence or lack of it in the tumor itself. This would tell the clini277
cian that the drug is not eective for that tumor, in that tissue, with those histopathological characteristics. Which in turn would save money, time and pain, leading to
possibly finding the drug that does have the desired therapeutic eect.
Now that this has been said, I understand the origin of this thread as someone coming
from this point. That is, how can we measure the antineoplastic in the microvasculature
of the tumor. For how much reaches the tumor's microvasculature may be indicative of
how eective is the drug. Without having to see a PD response from the tumor.
At least that is how I understood the origin of the thread. Maybe they should provide the
discussion group their reasons for seeking such data?
Alfredo R. Sancho,
USC PK-Imaging Ctr.
On 7 Mar 1997 at 09:58:37
Would the microdialysis suer of "clogging", at least in the case of tumors? That is, due to
the rapid and chaotic growth of tumor cells. I would hate to introduce the probe into the
tumor, which already is leaky in nature. But I would hate to implant the tissue or cell
around the probe and have it grow around it!
Alfredo R. Sancho
On 7 Mar 1997 at 10:03:00
Richard Scheyer
Restoration of the integrity of tumor vascularity might be different, and might vary
with tumor type.
Possibly of greater importance is what you wish to measure. Microdialysis is a useful probe of the extracellular space. While this is a region of interest for many drugs, it may not be of particular importance for antineoplastic compounds.
The above statement is not correct. The extracellular space [interstitial fluid space, IF +
microvascular space] is definitively of very major importance in drug transport into tumoral cells. We had recognized this on mechanistic grounds when we were studying the
mechanism of gallium localization to tumors, where we had suggested a pH gradient in the
interstitial fluid space due to lactic acidosis. See for example:
278
The Mechanism of Tumor Localization of Gallium-67 Citrate: Role of Transferrin Binding

and Eect of Tumor pH. S.R. Vallabhajosula, J.F. Harwig and W. Wolf. Intl. J. Nucl. Med.,
8, 363-370, 1981.
The importance of the IF space became apparent again when we were trying to model the
tumoral pharmacokinetics of two anticancer drugs, 5-fluorouracil (5FU) and cisplatin. We
had to incorporate another compartment between the vascular and the intracellular spaces
to account for the trapping of 5-FU in tumors. See:
Pharmacokinetic Imaging of 5-Fluorouracil in Tumors using 19F-NMR Spectroscopy. Walter Wolf, Victor Waluch, Cary A. Presant, Hyun K. Kim and Alfredo R. Sancho. Eurospin
Annual 1995-1996, p. 99-103. and Noninvasive 19F-NMRS of 5-Fluorouracil in Pharmacokinetics and Pharmacodynamic Studies. Walter Wolf, Victor Waluch and Cary A. Presant.
NMR in Biomedicine. In Press.
Perhaps the major dierence between studies in the CNS, as reported by Dr. Scheyer, and
in tumors, is reflected in what had been stated previously in that message:
After several hours, microdialysis concentrations reflect the extracellular space,
rather than the vascular compartment, although there may be some residual "leakiness"
for longer periods.
The time frame in tumors is much, much shorter. 5-FU, cisplatin, and presumably many
other antitumor drugs distribute by what is essentially a first passage process. That is one
of the major reasons we felt that the introduction of another process whose kinetics were
likely to be slow (equilibration between the interstitial fluid space and that of the microdialysis chamber) would not be conducive of measuring the fast kinetics of transfer between the 3 spaces that need to be considered when using PK to understand transport of
drugs into tumor cells: the vascular space, the interstitial fluid space and the intracellular
space.
This dierence in the time frames (seconds or minutes, rather than hours) is one of the
main reasons why we believe that the use of noninvasive methods is essential for capturing
the kinetics of drugs in tumors. Another major reason is that each tumor mass is dierent
- in structure, in vascularization, in the ratios of the various spaces - and therefore, in the
transport of drugs into tumor cells.
279

On 7 Mar 1997 10:03:48
Alfredo
Microdialysis probe is totally invasive. They need to be implanted surgically. The linear
probes are very small in dimensions so they cause minimal tissue damage. I do not recommend implanting them in humans at all because they can release the tumor cells. Histological studies in liver tissues done by Prof. Craig Lunte's group at University of Kansas have
shown that there is some necrosis at the implantation site in implantations of longer than
12 hours.
I don't know what you mean by "leakiness"? Is it the ultrafiltration property of the dialysis
membrane or leaking of tumor components? I am not very familiar with tumor physiology.
Amount of ultrafiltration depends on the membrane length, flow rate etc. Ultrafiltration is
not so significant in vivo.
47906
On 8 Mar 1997 at 22:42:46
Walter
I'm in complete agreement that the interstitial space is vital in modeling the kinetics. My
point was only regarding the presumed site of action.
Dept. Neurology, Yale School of Med., P.O. Box 208018, New Haven, CT 06520-8018 USA
280
On 8 Mar 1997 at 22:47:07
Alfredo,
1) If clearance is a way of calculating the amount of drug left in the blood compartment, hence how much is left in the tumor... what model are you using to compare the
tumor compartment?
I assume "compare the tumor compartment" means "predict the tumor compartment
amount (or conc)".
There is no tissue in the body that has the same infrastructure as that of tumors. We
could not even compare it to the tissue in which the tumor is in. Therefore, either
assumptions are made or invasive measurements are needed.
I agree with you that purely PK guided methods based on plasma concs cannot predict tumor concs. Early attempts (1970s) to explain delayed drug eects (digoxin and LSD were
the classical examples) nevertheless had some success in *describing* the time course of
drug *eect* using 2 compartment PK models based only on plasma concs of drug.
In 1979 Lew Sheiner formulated what is known as the eect compartment model which
uses the time course of drug eect and assumes a first-order process for equilibration of
active drug substance at the site of drug eect. Often a parametric model for the relationship between conc and eect is also assumed but this is not required.
Another important class of models used to explain delayed drug eects are based on a
physiological mechanism which is modified by the drug. Warfarin is the classic example
here but these so called indirect eect models have been used in lots of places where the
drug action can be understood in terms of an influence on the kinetics of a physiological
substance that mediates the observed drug response.
Some assumptions are involved but especially with the indirect eect models these are usually strongly supported by the known physiology/ biochemistry.
I personally don't have an aversion to making assumptions like these. They are not leap-offaith as you have suggested in an earlier posting (or at least they are dont seem so to me
and you have not given me any examples yet of such LOF assumptions).
Now if we agree that there is great patient inter-variability and that measurements of
clearance can be used as an indicator for tumor trapping of the drug. How accurate is
this?
I don't think accuracy is really the issue here. It depends on what you mean.
Is is not contradictory?
281
I don't see any contradiction (yet).

In the clinical scenario, would a one "common" or "average" dose -statistically calculated from previous patients- and noninvasive measurements be in order?
Sure. When planning the first dose for a patient you cannot do anything else but rely on
prior knowledge.
That is the first does measured at the tumor site itself, might be a indicator -if not
a predictor- of tumor response.
I quite agree. Once you have given a dose you can observe eects (and concs) and start
fine tuning how to achieve your therapeutic target (see Holford NHG The target
concentration approach to clinical drug development. Clin Pharmacokin 1995; 29:287-291
for details of such an algorithm).
Of course,just how good a predictor the observed concs or eects are for the response to
the next dose depends a lot on the drug. The etoposide example I cited in my previous
posting predicted that concs used to individualize clearance would be of more value than
attempting to individualize EC50 based on measured eects.
You see I put myself in the patients position... do I want to go through an entire protocol of chemotherapy without know if it is effective or not. Based solely on "statistical analysis" of previous patient tumor response data. Or do I want to take a single dose ("average" dose) and measure its presence or lack of it in the tumor itself.
This would tell the clinician that the drug is not effective for that tumor, in that
tissue, with those histo-pathological characteristics. Which in turn would save
money, time and pain, leading to possibly finding the drug that does have the desired
therapeutic effect.
The example you give is rather simplistic. If there was such a drug and such a non-invasive
test that could, on the basis of the a measurement made after the first dose, predict that
the drug would not be eective then I am sure it would be very helpful. But I do not know
of any real example of such a drug and test. Maybe a drug which exhibits multi-drug resistance (eg via P-glycoprotein transporter action) could show such an all or none penetration into a tumor. As you belong to the USC imaging group do you have any published examples of such phenomena?
It also seems unlikely that knowing the kinetics of the drug in the tumor would be all you
would need. The sensitivity (or resistance if you want to think of it like that) of the tumour to the drug as a function of the tumor conc would also need to be understood. So
you need a measure of drug eect as well as drug kinetics in tumor. Now, if you have the
time course of the drug eect on the tumor and you have the time course of plasma concs
a model connecting the two sets of observations can be built that can identify and distin282
guish the kinetic eg. CL, and dynamic eg. EC50, components of the response and the next
dose can be predicted on the basis of this improved understanding of what determines the
response in that patient.
Now that this has been said, I understand the origin of this thread as someone coming
from this point. That is, how can we measure the antineoplastic in the microvasculature of the tumor. For how much reaches the tumor's microvasculature may be indicative of how effective is the drug. Without having to see a PD response from the tumor.
Not having the tumor response only gives you part of the picture (see above).
At least that is how I understood the origin of the thread.
the discussion group their reasons for seeking such data?
Maybe they should provide
I agree that it would be useful if the person who started this thread (from Parke-Davis I
seem to recall) would join us again to oer some justification for wanting to determine
blood-free tumor drug concs. If anyone else is doing this type of thing it would be nice to
hear from you too. My impression has been that we have had technical suggestions for applying methodology but no examples showing that knowing tumor concs makes any dierence to drug development or patient care. I have given an example which predicts direct
patient care consequences from understanding anti-tumor drug eects based on *blood*
concs and *eects*. So lets hear from you tissue drug measurement guys!
Nick Holford
On 13 Mar 1997 at 15:19:19
Nick:
Pharmacodynamics and related topics If anyone else is doing this type of thing it
would be nice to hear from you too. My impression has been that we have had technical
suggestions for applying methodology but no examples showing that knowing tumor concs
makes any difference to drug development or patient care. I have given an example
which predicts direct patient care consequences from understanding anti-tumour drug
effects based on *blood* concs and *effects*. So lets hear from you tissue drug measurement guys!
Although I am not a "tissue drug measurement guy", these tissue-distribution studies are
extremely valuable, in that they identify non-linearities in drug uptake or drug eux from
normal tissues and tumors (i.e. as may be possible with p-glycoprotein mediated eux, as
283
you mention). A well-described example of non-linear tissue uptake is provided by Dedrick et al., who constructed physiologic pk models of methotrexate disposition.
I do not know of a single example of a PK/PD model utilizing tissue concentrations to predict ecacy or toxicity; however, this is not 'proof ' that such models would not be valuable (or should not be pursued)!
The development of rational therapeutic optimization strategies, based on PK/PD, requires robust (if not realistic) models. Investigation of possible areas of non-linear disposition is essential for the development of robust, useful models.
Having said this, it is worthwhile to note that any approach investigating tissue v. plasma
concentration relationships should attempt to make said determinations at a range of
doses (or if possible, concentrations). Evaluation of tumor distribution at a single, low
dose (as suggested by someone along this string) *may* provide an inaccurate assessment
of tumor distribution resulting from therapeutic doses.
Joseph P. Balthasar, Ph.D.
Assistant Professor, Department of Pharmaceutics and Pharmaceutical Chemistry, 421
Wakara Way, Room 316, University of Utah, Salt Lake City, Utah 84108
On 14 Mar 1997 at 10:55:02

So lets hear from you tissue drug measurement guys!
Thank you. I note however that you are an indirect tissue measurement guy and not really
a representative of the wet tissue group I was hoping would contribute at this point. However, many of your remarks have relevance to the study of PK on an organ or regional basis.
Perhaps the most cogent reasons why we believe that relying on noninvasive methods
for generating data are: A) The living system is, by its very nature, a dynamic system. Precise knowledge of the kinetic parameters is probably as important - and sometimes likely to be even more important - than knowledge of the thermodynamic values.
Thermodynamic values in this context means the same as pharmacodynamics to me. My

earlier example of etoposide PKPD (Karlsson et al). illustrated exactly this point. PK
(clearance) was a more useful predictor of individual response than PD (EC50).
284
Kinetic data, however, must be generated under conditions where the system to be studied is not perturbed - e.g., that these kinetic events are not modified during the
process of attempting to measure them.
The latter constraint is only a problem if your kinetic model does not include knowledge
about "system perturbations". So called physiological PK models attempt to do this (at
least for blood flow and organ size perturbations).
B) Noninvasiveness does, by its very nature, not perturb the system from
trying to generate data.
which one is
I am not familiar with your technology but assuming it is along the lines of PET scanning
etc I would say that the while not very invasive (in contrast to direct brain sampling) it is
quite interventional (scanner etc). Activities such as lying down e.g. to be scanned, can
change systemic PK.
C) The collection of data from a single individual, and especially, measuring in that
same individual changes induced by various perturbations, yields information that is
often lost when analyzing pooled data. This is because such pooled data have all the
interindividual variabilities superimposed on them. This topic was well documented in
the PhD dissertation of R. Ricardo Brechner (1986), and published in J. Pharm. Sci.
53:873-877, 1986.
The disadvantages of naive pooled data approach have been discussed at length in the
PKPD literature and popln approaches to understand responses in individuals are widely
used e.g. see the book Variability in Drug Therapy edited by Rowland, Sheiner and Steimer. Raven Press 1985 (based on a meeting in Rome in May 1984). At the second COST B1
program meeting on "Measuring and managing variability in response, concentration and
dose" was held in Geneva, Feb 1997, and included a review by Karlsson on advances in the
anti-cancer area.
D) Inasmuch as tumors, by their very nature, do not obey precise rules of growth, development, etc., it is critical to understand the degree of exposure of each tumor and
or metastatic site to develop proper chemotherapeutic planning.
It may be that it is feasible on a tumour specific basis to plan chemotherapy using tumour
localised PK data. I acknowledge your P<0.000001 statement below but this is not the
same as prospectively demonstrating the value of the intervention as the history of therapeutic drug monitoring has shown.
We now have a letter appearing in this month's Annals of Oncology that states that response of a tumor to 5-Fluorouracil requires that there are 3 independent conditions
that have to be met simultaneously for this drug to be active. These 3 conditions are:
1) There must be trapping of 5-FU in the tumor. 2) The tumor must have adequate perfusion to make such trapping possible. 3) The tumor type must be of a responsive type to
make such trapping effective.
285
Fine. But note that condition 1 is rather general. Its not an all or none world. The relation
between extent of trapping and tumour response needs to be established (e.g. in terms of
Emax, EC50) and in particular what is the variability in response given the same trapping
from one treatment occasion to the next. Unless this variability is suciently small there
will be no benefit from attempting to individualise doses for a specific patient.
My impression has been that we have had technical suggestions for applying
methodology but no examples showing that knowing tumour concs makes any difference to drug development or patient care.
We do have examples that show that drug trapping in tumors makes a significant difference on patient care. We have shown [The Lancet, 343:1184-1187, 1994] that there is a
very strong association between the trapping of 5-FU in a variety of human tumors and
response [p<.000001]. Our clinicians have been making use of whether a patient traps
5-FU to make decisions on patient treatment, as well as to assess whether a given modulator (e.g., methotrexate, interferon, etc.) is worth using in a particular patient.
Apart from the statistical correlation what can you say about the prospective benefit of
making decisions about 5-FU? As noted above is this reproducible for a specific patient in
settings where repeat treatments are usually employed? If single shot treatments are used
then of course it is hard to understand how any individualisation based on studying the
drug in that tumour can be of use (apart from the use of tracer doses which may be misleading for non-linear disposition processes).
Our studies showing that the targeting of cisplatin [studied using 195mPt- cisplatin]
to brain tumors is a function of both the method of drug administration [see Cancer
Research 49:1877-1881, 1989] and modifiers of osmolality [Proc. Am. Assoc. Canc. Res.
36:360(2142), 1995] are being utilized by clinicians to achieve significant success in
the treatment of patients with high grade astrocytoma.
Thank you for the info.

This thread has revealed that dierent groups within the overal field of pharmacology are
often unaware of the advances made by other disciplines. I certainly admit to such ignorance and I am delighted to have learned from the contributions to this thread.
Nick Holford
286
On 14 Mar 1997 at 10:55:33

Although I am not a "tissue drug measurement guy", these tissue-distribution studies
are extremely valuable, in that they identify non-linearities in drug uptake or drug
efflux from normal tissues and tumors (i.e. as may be possible with p-glycoprotein mediated efflux, as you mention). A well-described example of non-linear tissue uptake
is provided by Dedrick et al., who constructed physiologic pk models of methotrexate
disposition.
This point is well taken. I wonder if this is the main reason why the "tissue measurement
guys" do it? What successes have they had?
I do not know of a single example of a PK/PD model utilizing tissue concentrations to
predict efficacy or toxicity; however, this is not 'proof' that such models would not
be valuable (or should not be pursued)!
I accept the lack of proof concept. But on the other hand people have been at this tissue
PK game for decades (Dedrick was doing his stu in the '60s amd '70s). I am not aware
that even the Dedrick MTX example had a clinical spino but I would be happy to be corrected on that. So just how has tissue sampling helped in understanding human clinical
pharmacology?
Having said this, it is worthwhile to note that any approach investigating tissue v.
plasma concentration relationships should attempt to make said determinations at a
range of doses (or if possible, concentrations). Evaluation of tumor distribution at
a single, low dose (as suggested by someone along this string) *may* provide an inaccurate assessment of tumor distribution resulting from therapeutic doses.
Agreed.
Nick Holford
Dept Pharmacology & Clinical Pharmacology
University of Auckland, Private Bag 92019, Auckland, New Zealand
287
S EC T I O N 33
Hydroxyurea Protein Binding

On 20 Oct 1997
Has anyone information regarding hydroxyurea protein binding? Determination of protein binding of hydroxyurea with Centrifrees yields a slightly, but constant, negative
number. We see the same over a wide range of concentrations done in replicates of 5. Has
anyone seen the same with other compounds that exhibit little to no protein binding? References?
Steven J. Weber
On 21 Oct 1997
How are you measuring the hydroxyurea? If you are using radioactivity, it is possible that
the Centrifree tubes are removing a quenching substance. You may wish to verify your
quench curve for ultrafiltrated and non-filtered samples. Occasionally, investigators rely
too heavily on external quench correction, perhaps forgetting that the underlying eciency relationships are matrix dependent.
If you are using HPLC, are you observing a fixed increase in assayed concentration (i.e.,
ultrafiltrated recovery = control recovery + some intercept) or a fractional increase in assayed concentration (e.g., ultrafiltrated recovery = 110% of control)? If you observe a fixed
increase, you may be extracting an interfering substance with your ultrafiltration step. If
you see a fractional change (i.e., a matrix eect), you may wish to check for increased postfiltration extraction of hydroxyurea, decreased post-filtration extraction of an internal standard, extraction of a substance which interferes with an internal standard).
Joseph P. Balthasar, PhD
Assistant Professor, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah
288
S EC T I O N 34
Ideal Body Weight Calculations

On 24 Feb 1997 at 10:41:38
I am searching the literature for alternative equations for the estimation of ideal body
weight to use in the calculation of estimated Creatinine Clearance and to use with population estimates of volume of distribution for aminoglycosides, etc. Thanks in advance for
any information provided...
Del Tippey R.Ph., M.S.S.M.
DCH Regional Medical Center, 801 University Blvd. E., Tuscaloosa,AL 35405
On 25 Feb 1997 at 12:34:46
I suggest you read a consensus document that was posted recently on the pulsing dosing of
aminoglycosides. In an appendix at the end of this document you will find the desired
equations and more. The address is: http://www.pharmpk.com/consensus/odacd.html
Nasr Anaizi, PhD RPh
Univ of Rochester Med Cntr
On 25 Feb 1997
The following equation can be use :

LBW (males) = 50 kg + 2.3 kg per inch over 5 ft
LBW (females) = 45.5 kg + 2.3 kg per inch over 5 ft
Please also see page 420, Applied biopharmaceutics and pharmacokinetics Leon
Shargel and Andrew B.C. Yu for detail
Masood Bhatti
289
On 25 Feb 1997 at 12:36:25
The following is the equation that I always use. It has been verified in infants, children
and adults.
BSA = [see correction below - db]
Haycock GB, Schwartz GJ, Wisotsky DH: Geometric method for measuring body surface
area: a height-weight formula validated in infants, children, and adults. Journal of Pediatrics 1978;93:62-66.
S525 College of Pharmacy, Asst. Prof., College of Pharmacy, Iowa City, IA 52246
On 26 Feb 1997 at 10:42:01
Thank you for the reply, but are you aware of equations that estimate ideal body weight
for patients that fall outside this range -i.e. height < 60 inches, below knee amputees, etc.
Thanks in advance...
On 27 Feb 1997 at 10:34:43
Isn't there a misprint in your formula?

In Gibaldi, M., Biopharmaceutics and Clinical Pharmacokinetics. Philadelphia: Lea & Febiger, 1984, p. 211 we find almost the same formula except the coecient:
BSA(m2)=WT^0.5378*HT^0.3964*0.024265
290
On 27 Feb 1997 at 10:34:57
Thanks for the info. Also thanks for the info you sent earlier regarding Vancomycin Vd.
I'm going to check out this reference. BTW, does the ** refer to exponent?
[** is exponent, also ^ - db]
On 28 Feb 1997 at 11:51:10
Yes, the last term should be 0.024265.

Also, the incorrect response was sent, my full message (but inadvertently not sent) was:
Ideal body weight (18 years of age and older):
Males: 50 Kg + (2.3 Kg for each inch over 5 feet)
Females: 45.5 Kg + (2.3 Kg for each inch over 5 feet)
(Unable to find primary reference.)
Ideal body weight (Children age 1 - 18):
Under 5 feet:
IBW (Kg) = (Ht in cm)**2 * 0.00165
5 feet or taller: Males: 39 Kg + (2.27 Kg for each inch over 5 feet)

Females: 42.2 Kg + (2.27 Kg for each inch over 5 feet)
Traub SL and Johnson CE: Comparison of methods of estimating
creatinine clearance in children. Am J Hosp Pharm 1980;37:195-201.
Body surface area:
BSA (m2) = (Wt in Kg)**0.5378 * (Ht in cm)**0.3964 * 0.024265 m2
Haycock GB, Schwartz GJ, Wisotsky DH: Geometric method for measuring body surface
area: a height-weight formula validated in infants, children, and adults. Journal of Pediatrics
1978;93:62-66.
291

S525 College of Pharmacy, Asst. Prof., College of Pharmacy, Iowa City, IA 52246
On 5 Mar 1997 at 11:36:45

I would like to examine the various BSA formulas; we are having quite a argument at
work over this. Historically our hospital utilized the charts or calculators found in
many texts that are based on the 1916 Annals of Internal Medicine formula of Dubors
and Dubois. When pharmacy became more involved we used the numbers in our computer
software package. This formula involves the square root..... I wish I had the facts
here at home. Needless to say, the numbers come out different; I expect if I use the
formula in this newsgroup I will get a third figure to work with. I am not a scientist, just a pharmacist, but I would like to know alot more about the different bsa
formulas and their relationship, if any. Likewise, what happens to the toxicity of my
chemo doses if I use one over the other. I guess I'm really looking to defend the
software program and prove the non clinicians at the hospital they should stick to
their areas of expertise.
For the specific area of cancer chemo you should read Reilly & Workman Normalisation
of anti-cancer drug dosage using body weight and surface area: is it worthwhile? Canc Chemoth Pharmac 1993; 32:411-418 They cover in depth the issues you mention above. Unfortunately they do not recognise that PK is determined by volume of distribution (as well as
other things) and they only discuss scaling that would be relevant to decisions that rely on
clearance i.e. steady state concs or AUC. See Holford Clin Pharmacokin 1996;30:329-332 for
a small amount of discussion of volume scaling.
The bottom line is that there is almost no evidence that using BSA or any other measure
of size improves dose prediction for adults. The issue becomes important when trying to
scale adult doses for paediatric use.
Nick Holford
292
S EC T I O N 35
In Vitro to In Vivo Scaling for Metabolic

Parameters
On 22 Sep 1997 at 10:20:00
I am developing some human PBPK models for some volatile organic compounds.I have
Km and Vmax data based on in vitro human liver microsomes.When scaling to in vivo I
need a value for mg of microsome per gram of liver. I have been using a range of 10-50mg
per g. Can anyone oer a better estimate or point me in the direction of some literature? I
have found a couple of papers for rat data but none for humans.
Alex MacDonald
Graduate Student, Dept of Medicine and Pharmacology, University of Sheeld UK
On 23 Sep 1997 at 10:48:32
A good article on in vivo-in vitro correlation for human liver is Prediction of in vivo drug
metabolism in the human liver from in vitro metabolism data, Takafumi Iwatsubo et.al.
Pharmacol. Ther. 73, no. 2, 1997 147-171
47906
293
S EC T I O N 36
Infusion rate versus Concentration

On 7 Mar 1997 at 10:01:31
This is for a colleague of mine.

A drug is administered by rapid bolus (rate defined) at several dosages and blood collected
for analysis of test article concentration at several intervals following dosing, and the
blood drug concentration vs. time profile defined. Based upon this data, I would like to
model the blood drug concentration vs. time profiles for the same (or lower) dosages administered at dierent rates (slower or faster). I'm looking for a pharmacokinetic model
which will permit me to model the eects of dosage, dosage rate, and blood drug
concentration vs. time.
Vinay.Desai
On 8 Mar 1997 at 22:43:23
I may be missing something in your question but any PK model for an infusion (apart
from those parameterized in the antique A,alpha,B,beta style) will allow the dose (or dose
rate) and duration to be defined as part of the model and it should be straightforward to
estimate PK parameters from your data and subsequently simulate profiles with dierent
doses and input rates.
Nick Holford
On 13 Mar 1997 at 15:18:49
You need a model that is a good description of initial bolus kinetics to do this. I addressed these issues in a recent paper:
294
Upton RN. A model of the first pass passage of drugs from their intravenous injection site
to the heart - parameter estimates for lignocaine. Br J Anaesth 77: 764-772 (1996)
You also might like to look at:
Wada DR, Ward DS. The hybrid model: a new pharmacokinetic model for computercontrolled infusion pumps. IEEE Transcripts of Biomedical Engineering 1994; 41: 134-42.
Krejcie TC, Henthorn TK, Shanks CA, Avram MJ. A recirculatory pharmacokinetic
model describing the circulatory mixing, tissue distribution and elimination of antipyrine
in the dog. Journal of Pharmacology and Experimental Therapeutics 1994; 269: 609-616.
Dr Richard Upton
Senior Hospital Scientist/Senior Lecturer, Department of Anaesthesia and Intensive Care,
Royal Adelaide Hospital/University of Adelaide, SA 5005 Australia
295
S EC T I O N 37
Interspecies Scaling of Lung Surface Area

On 23 Jun 1997 at 12:14:08
I am about to carry out some interspecies scaling in mammals for lung concentrations following inhaled administration.
Rather than using volumes in the scaling, it was thought more appropriate to use
concentration of drug per square meter. However I am finding it very dicult to find references and values of the total surface area of lung, alveoli and bronchi, in rat, pig, dog, rabbit and humans.
J. Emelogu
On 25 Jun 1997 at 10:30:52
The following table appeared in Assessing the use of pharmacokinetic models in risk assessments on inhaled toxicants. MaryJo Miller. Dissertation submitted to the State University of New York at Albany, School of Public Health Sciences Environmental Health
and Toxicology (1992).
296
Surface Area (cm2)
Respiratory Tract
Region
Mouse
Rat
Human
Nasopharyngeal
0.94
11.6
117
Tracheobronchial
3.2
37.6
5036
Pulmonary
292
3424
635545
Thoracic *
295
3462
640581
Total **
296
3473
640758
* Thoracic = Tracheobronchial + Pulmonary

** Total = Nasopharyngeal + Tracheobronchial + Pulmonary
Adapted from US Environmental Protection Agency (US EPA). 1989. Interim methods
for development of inhalation reference doses. Washington, DC: Oce of Health and Environmental Assessment. EPA/600/8-88/066F and personal communication with Ms. Margaret Menache, NSI Technology Services (under contract to US EPA), on May 3, 1991.
Jack Cook
On 25 Jun 1997 at 10:31:1
The appropriate reference is the CRC Handbook of Toxicology, Chapter 5 (Inhalation

Toxicology); Eds. Derelanko MJ and Hollinger MA, 1995.
Anup Zutshi
297
S EC T I O N 38
IV Cannulas in Rats
On 5 May 1997 at 13:23:51
We are doing PK-PD work in rats and try to use the same rats for longitudinal studies. For
that we need to maintain the iv. cannulas (indwelled into the Jugular vein) for several
weeks. However, we experience constant technical problems due to plagues/ clotting/
blockade of the cannula. To prevent this problem we use heparinized PVP solution. Another problem is that after a while the rat managed to reach the cannula and to pull it out
of the vein. The cannula is exteriorated at the lower dorsal part of the neck, and it is secured with 3 sutures at that attach the PE 50 cannula to the vein, the muscle and the skin.
Does any of you have experience with prolonging the "life" of the cannula.
Amnon Homan, Ph.D.
Dept. of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, POB
12065, Jerusalem 91120 Israel
On 6 May 1997 at 11:53:52
Usually, increased frequency of cannula care increases the long-term cannula patency. We
use heparinized(20-50 U/ml)sterile isotonic saline to flush the cannula everyday. A blunt
needle (23G1) and 1 ml syringe are used to flash the cannula. The instilled solution is withdrawn. The aspirated fluid/blood should be discarded as it may contain small thrombi. The
cannula is flushed with saline to clear it of blood, and refilled with fresh heparin solution.
The cannula should be flushed with a volume of solution slightly larger than the volume of
the cannula. Forceful injection of saline (0.2 ml) may break up a obstruction with the risk
of a trapped emboli in the vasculature of the lung. Of course the cannula has to be inside
the vein to get blood.
Heparinized PVP solution oered no better advantage to us than heparinized saline.
298
We usually exteriorize the jugular vein cannula by subcutaneous tunneling from the vascular incision site to the back of the neck (midway and dorsal to the ears). The cannula is
clipped with the skin to secure the position. The exterior length of the cannula is about 2
inches and plugged with a blunt quilting pin (0.5 inch)!
Some useful information can be found in the following article: Cocchetto et al. J Pharm
Sci 72(5):465-492, 1983.
M. Delwar Hussain, Ph.D.
School of Pharmacy, University of Wyoming, Laramie, WY 82071-3375
On 6 May 1997 at 11:54:41
Here are some suggestions for jugular vein catheters in rats:

1.
Be sure to flush the cannulas at least once (preferably twice) daily with heparinized saline (first thing in the morning and just before leaving for the day)
2. Exteriorize the catheter further down the back so the rats can't reach behind their
heads
3.
Increase the conc. of heparin in the catheter
4. Redesign your catheter (to avoid as many tubing joints as possible)

5.
I have used a single piece of silastic tubing (about 6" long) with a large bead of silicone
placed on the tubing about 1" from the end. The catheter is pushed in up to the silicone bead which is then sutured in place subcutaneously. The tip that enters the heart
is beveled slightly. The catheter is exteriorized around the back of the neck and
plugged with part of a blunt needle that has been blocked with silicone. I have never
had one of these catheters pulled out and I have had good results keeping them open.
6. Also, sometimes what can appear to be a blocked cannula can often be a constriction
related to the animal's position. Sometimes moving the animal a little bit or gently manipulating the area transversed by the catheter can eliminate the constriction.
Paul Damian PhD, MPH
299
Program Coordinator, Western Region, Food Animal Residue Avoidance Databank, Dept.
of Environmental Toxicology, University of California, Davis, CA 95616
http://farad.aaa.ucdavis.edu (FARAD)
On 12 May 1997 at 15:55:20
I have used an indvelling plastic catheter on rats up to a couple of weeks. To keep the rats
from chewing on them we made a saddle like construction in leather. It has a connection
at the back for a steel-coil, in which the catheter can run. This steel-coil can be connected
to the top of the cage, thus enabeling a constant access to venous blood. When not doing
experiments the plastic catheter can be keept under the saddle. If the rats are keept with
the saddles pre-op. there are no problems post-op.
Magnus Hultin, Ph.D.
Dept of Medical Biochemistry and Biophysics
Umea University, Umea, Sweden
On 19 Jun 1997 at 13:29:04
I haven't read all of the responses yet so I don't know if you've heard this response yet. I
perform dozens of vascular surgeries, and usually what we use to keep the catheter patent
is heparanized saline at (100U/ml. It is neccessary to flush the catheters every day in order
to maintain it patency over time. I also use a tether spring system to protect the catheter.
if you are not familiar with this system, it is a stainless steel spring that is placed over the
catheter and is stitched to the animal's back. Because it is made of steel the animal cannot
get to the catheter. It is also designed to be able to accomodate a spring if neccessary. I
have recently investigated a company called Access Technologies based in Virgina that
have developed silastic catheters with a rounded end. They claim that the rounded end
damage the vessels less upon insertion and therefore can maintain patency for a greater
length of time.
Danytza Ward
300
On 13 May 1997 at 11:25:05
About the issue of long term cannula in rats...

We place the cannula (Clay Adams, PE-50) in the rats right jugular. Pass it subcutaneously
to the mid-scapular region of the rat, where we suture it into place using silk thread. The
"free" end of the cannula we first tap it shut with clay or putty, sealing it and avoiding loss
of blood. Then we re-insert it sub-cutaneously into the back region of the rat. All along
we would occasionally flush the cannula with heparinized normal saline.
This has proven satisfactory, for the cannula does not become obstructed nor can the rat
reach into its own body to bite the cannula. We have been able to keep this setup for several days with a high rate of success.
Also, we found that "installing" odd contraptions around or on the rat to protect the cannula, alter the rats stress level. Which you all know may very well aect the kinetics of the
studied drug, due mainly to the physiological changes in the rat.
Alfred R. Sancho
USC PK-Imaging Ctr., Los Angeles, CA
301
S EC T I O N 39
Jack Knife Mean

On 23 Oct 1997 at 09:38:24
Would anyone teach me how to calculate the Jack Knife Mean (for estimating the Standard deviation of Harmonic Means) or give me a reference to any book on how this calculation is done
Raul Valverde
Phoenix International Life Sciences Inc.
On 24 Oct 1997 at 09:40:05
A reference for calculating pseudo-standard deviations for harmonic mean half-lives is:
Lam FC, Hung CT, Perrier D (1985) Estimation of Variances for Harmonic Mean Halflives J Pharm Sci 74:229-231
Horst Welker
F. Homann-LaRoche Ltd., Clinical Pharmacology, PDC5, CH-4070 Basel, Switzerland
On 24 Oct 1997 9:39:00
The following reference describes calculation of the harmonic mean and corresponding
variance:
Lam et al: Estimation of variance for harmonic mean half-lives. J Pharm Sci 74:229-230,
1985.
Gary A. Thompson, Ph.D.
Clinical Pharmacology, Procter and Gamble Pharm., 11450 Grooms Rd., Cincinnati, OH
45242
302
On 24 Oct 1997 09:43:03
I have always found Efron's paper 'A leisurely look at the bootstrap, the jacknife and crossvalidation' The American Statistician 37: 36-48, 1983 a worthwhile source of information. It
is well written and at a level which I feel comfortable with.
Leon Aarons
M13 9PL, U.K.
303
S EC T I O N 40
ka/k Values for Immediate Release

Formulations
On 7 Oct 1997 at 10:53:31
I need to know does anyone have a reference that clearly states what the ratios of ka/k
would be for a drug exhibiting 1-compartment first order absorption kinetics to be considered an immediate release formulation. The values for these ratios should be consistent
with the half-life of absorption being less than Tau(dosing interval) when the formulation
is given in a multiple dosing regimen.
Andre Jackson
On 8 Oct 1997 at 11:03:12
I would say that a ka/k ratio between 5-10 would be satisfactory. I am not clear about your
question reg: consistency with half-life of absorption being < than Tau. In most practical
cases Tau can be selected to be > the time needed for absorption.
Srikumaran Melethil, Ph.D.
Professor of Pharmaceutics and Medicine, School of Pharmacy (Room 203-B)
University of Missouri-Kansas City, 5005 Rockhill Road, Kansas City, MO 64110
On 10 Oct 1997 at 14:50:30
One of our papers entitled:

M.L. Kaltenbach, S.H. Curry, and H. Derendorf. Extent of drug absorption at the time of
peak plasma concentration in an open one-compartment body model with first order absorption. J. Pharm. Sci. 79 (5) (1990) 462.
may help you in determining the ka/k ratio needed for a drug exhibiting 1-compartment
first order absorption kinetics to be considered an immediate release formulation.
304
I can also remember that Dr. Macheras published an extension to this work for drugs exhibiting 2 compartments characteristics in the same journal a few years later.
Matthieu L. Kaltenbach, PharmD, PhD
Laboratoire de Pharmacocinetique, UFR de Pharmacie, Universite de Reims Champagne
Ardenne, 51 rue Cognacq-Jay, F-51100 Reims, FRANCE
305
S EC T I O N 41
Ketamine Pharmacokinetics
On 8 Jul 1997 at 09:36:57
I am writing a modeling program for the Psion computer. I have been unable to find complete 3 compartment data on the following drugs - does anyone have the data or know
where to find it?
Ketamine
Alfentanil
Fentanyl
Obviously I need the compartment volumes, v1, v2, v3, and the coecients k10, k12, k21,
k31, k13. Failing that Clearances and volumes should be enough to calculate the coecients.
Dr Simon Ashworth
Dept Anaesthetics, Hammersmith Hospitals NHS Trust, LONDON
On 9 Jul 1997 at 11:33:11
Fentanyl
Olkkola K.T. et al. in Clinical Pharmacokinet. 28: 385-404, 1995
Ketamine
White P.F. et al. in Br. J. of Anaesth. 57: 197-203, 1985
A review article published for the above two drugs before these dates can help you identify
and cross-reference. This article is
Ghoneim M.M. and Korttila K. in Clinical Pharmacokinetics 2: 344-372, 1977
Alfentanyl
306
Bodenham A and Park G.R. in Clinical Pharmacokinetics 15: 216-226, 1988

Anup Zutshi
On 9 Jul 1997 at 11:33:45
Here are references that I got in Dr. J.F.Coetzee's Simulation + CACI Program, STELPUMP:
Ketamine
Bomino et al. Clin Pharmacol Ther 1984; 36: 645-653
Alfentanyl
Maitre et al. Anesthesiology 1987; 66: 3-12
Scott JC, Stanski DR. J Pharm Exp Ther 1987; 240:159-166
Fentanyl
Shafer et al Anesthesiology 1988; 69: A460
Scott et al. J Pharm Exp Ther 1987; 240:159-166 (keo from article?)
Stefan Harms
On 10 Jul 1997 at 15:56:08
According to fentanyl you will find first informations on pharmacokinetic rate constants
in this articles:
Shofer SL; Varvel JR, Anesthesiology 1991; 74: 53-63
Lemmens HJM; et al., Clin Pharmacol Ther 1994; 56: 261-71
Willi Cawello PhD
Schwarz Pharma company, D40789 Monheim am Rhein, Germany
307
On 10 Jul 1997 08:29:08
The following references may be useful:

1.
Youngs EJ. Shafer SL. Pharmacokinetic parameters relevant to recovery from opioids
Anesthesiology. 81(4):833-42, 1994
2. Lemmens HJ. Dyck JB. Shafer SL. Stanski DR. Pharmacokinetic-pharmacodynamic

modeling in drug development: application to the investigational opioid trefentanil.
Clinical Pharmacology & Therapeutics. 56(3):261-71, 1994
308
S EC T I O N 42
Ki Inhibition Constant
On 23 Oct 1997 at 09:46:38
When preforming inhibition studies in vitro with human liver microsomes, one can determine a Ki value, that is the concentration of the inhibitor that reduces the formation
speed of the metabolite (for the pathway of interest) with 50 % at low substrate concentrations ([S]<dissociation constant, or an anity constant, of the inhibitor-enzyme complex.
This Ki value, once determined for a specific inhibitor and a specific iso-enzyme should be
constant. In the literature however the Ki varies with the reaction studied.
Is this Ki value, although theoretically constant, dependent on the substrate and the reaction studied ? If so, how can one explain this phenomenon ? Is there an explanation on
molecular level ?
Alex Hemeryck, Ph.D. student
Pharmacist, Heymans Institute of Pharmacology, University of Ghent, Medical School, De
Pintelaan 185, B-9000 Gent
On 24 Oct 1997 at 09:39:41
Your definition of Ki is really the definition for the IC50 of an inhibitor in the presence of
a specific substrate.Ki can be calculated from the IC50 using the equation: Ki=IC50*Km/(S+Km), where S is the conc. of substrate, and Km is the substrate conc. (in the absence
of inhibitor) at which the velocity of the reaction is half-maximal. For derivation and molecular basis, see PRINCIPLES OF DRUG ACTION, third ed., Pratt and Taylor. The
Ki of an inhibitor for inhibition of a particular substrate (fixed Km) is constant. For a different substrate, Km is dierent, and so is the Ki.
Arnab Mukherjee
Univ. of Tennessee, Memphis
309
On 27 Oct 1997 at 10:49:36
In reply to the answers I received, I would like to ask the following question:
Fluoxetine and paroxetine are known as potent inhibitors of CYP2D6 substrates. Ki
value's in the range of 0.1 - 1 M are found in the literature for CYP2D6-substrates such as
desipramine. Also in vivo interactions between these two SSRI's and CYP2D6 substrates
have been described. In fact these interactions could be predicted from the Ki value of the
SSRI, in combination with its plasma levels and plasma:liver partition coecient. Suppose
one finds a Ki value of the SSRI's for another substrate studied, wich is ten times higher
than for desipramine (due to the fact that the substrate studied has a much lower Km than
desipramine), what should be expected in vivo for this new substrate ?
Alex Hemeryck
Pharmacist, Heymans Institute of Pharmacology, University of Ghent, Medical School, De
Pintelaan 185, B-9000 Gent
310
S EC T I O N 43
Levodopa Concentration Fluctuations

On 27 Jul 1997 at 15:01:27
I am looking for some information about clinically relevant plasma Levodopa concentrations fluctuations i.e. What percentage change in steady-state concentrations would be
considered clinically relevant, given the high variability of Levodopa and the unique PK/
PD relationship of Levodopa.
Malcolm Bohm
Clinical Pharmacokineticist
On 6 Aug 1997 at 11:04:15
On the face of it, I do not think there is any very meaningful answer to your question
about "percentage change in steady state concentrations". Much of the clinical response to
levodopa is predictable from the overall time course of plasma levodopa concentration.
The pattern of the response changes over time (described as "stable" and "fluctuating"
types of response). Provided levodopa concentrations remain above the EC50 for that
patient the response is essentially indpependent of the fluctuation in plasma
concentration because the conc-eect relationship is steep (Hill coecient 3 or greater).
Adverse eects (eg dyskinesia) are not clearly correlated with the EC50 for beneficial effects so finding an optimal concentration for an individual is not easy especially in the
"fluctuating" patient. It is important to recognise also that there is a component to the
inter-dose time course of Parkinson's disease that is not predictable from plasma concentrations of levodopa (or other large neutral amino acids) which has been called "y0yo-ing".
The "on/o " phenomenon is also used to describe this eect but it is frequently confused
(not surprisingly) with the rapid but predictable "end of dose" deterioration that occurs
when eect site concs fall below the EC50.
311
I suggest you take a look at the review by Nutt and Holford (1996) which attempts to link
the clinical neurology and clinical pharmacology of levodopa and discusses the above issues at some length.
Nutt JG, Holford NHG. The response to levodopa in Parkinson's disease: imposing pharmacological law and order. Ann Neurol 1996; 39:561-73.
Nick Holford
On 11 Aug 1997 at 13:50:38
Dr. Peter Silverman, at the U. of Texas Health Science Center in Houston has published a
proposed animal model for the "on-o " eect seen with levodopa.
You might find his work interesting.
P. Silverman, Eur. J. Pharmacology, vol 242, 31-36, 1993. On-O eect of dopamine receptor
agonists in the hemiparkinsonian rat.
Vahn Lewis
312
S EC T I O N 44
Log Trapezoidal Rule

On 12 May 1997 at 15:57:45
I have some question on log-trapezoidal rule. Is there another name(formal name) of

"modified log-trapezoidal rule"(in up phase, linear trapezoidal; in terminal phase, log trapezoidal)?
And I have read one protocol that use log-trapezoidal rule to calculate AUMC. I don't understand it's meaning.
Is it possible to use log-trapezoidal rule to calculate AUMC?
I think in calculating MRT or Vdss, in spite of using AUC calculated by log-trapezoidal,
AUMC must be calculated by linear trapezoidal rule.
Young-Joo Lee
Researcher, Pharmaceutic Lab., College of Pharmacy, Seoul National University, San 56-1,
Shillim-Dong, Kwanak-Gu, Seoul, 151-742, KOREA
On 13 May 1997 at 11:26:03
Since AUMC is the area under the time*Cp curve, and the tail of the latter behaves (irrespective to the route of administration) like a (disturbed) monoexponetial function, the
combined trapezoidal rule (linear in the ascending part and log-linear in the descending
part of the curve) is applicable in general. Of course, the accuracy of this approximation is
significantly less than in case of AUC. Moreover, the random noise in Cp will disturb the
estimates of AUMC obtained by the trapezoidal rule in much more extent as compared to
AUC. Therefore, to get reliable estimates of MRT and Vss you need much more precise
data and more data points than to estimate CL.
Vladimir Piotrovsky, Ph.D.
313
On 14 May 1997 at 15:59:10
There is no dierence in the way AUC and AUMC should be calculated; both are areas of
a continuous function, which can be calculated mathematically if the functions are known.
If only data points are known, the areas can be estimated by various methods; in general,
the linear and log trapezoidal rules are the preferred methods because of their robustness
(more sophisticated methods may be more sensitive to outliers, et cetera). The choice between the linear and log trapezoidal rule depends ONLY on the expected profile BETWEEN the data points. If the profile is expected to be almost linear, or if the profile is
expected to be higher than the linear interpolation, then the linear rule is preferred. If the
profile is expected to follow a curve below the linear interpolation, the log rule should be
used. The latter is obviously the case during exponential decline. The simple rule of using
the linear rule during the inclining parts, and the log rule during the declining parts of the
curve, can be used in most cases. A better criterion for choosing between the linear and
log rule can be found in my paper in J.Pharm.Sci. 1985; 74:793-794.
Please note the problems of extrapolation if the last sampling point is not very low. The extrapolation errors for AUMC are much more pronounced than for AUC. As a result, the
calculated MRT may be inaccurate.
Johannes H. Proost
314
S EC T I O N 45
Median and Mean

On 20 Oct 1997 at 12:36:14
Would anyone teach me which parameter, mean or median, is usually used in evaluating
the typical plasma profile and PK population parameters for the data has the large interindividual variability.
Yasuo Koyama
Back to the Top

On 20 Oct 1997 16:06:57
Whether to choose the median or mean depends on the distribution of the data. Typically, pk parameters are log-normally distributed, in which case the most appropriate parameter is the median. Unfortunately, most scientists mis-represent data by reporting it as
though the data came from a normal distribution. Perhaps the simplest way to determine
whether a distribution is normal or log-normal is to transform the data using the natural
log and then use a goodness of fit test for the normal distribution. A useful reference in
this regards is R.B. D'Agostino and M.A. Stephens: Goodness of Fit Techniques. Marcell Dekker, New York, 1986. Another good reference is LF Lacey et al: J Biopharmaceutical Statistics 7, 171-178, 1997.
City, MO 64134
On 20 Oct 1997 14:07:29
Usually the median is better, as things are usually more symmetrically distributed about it.
Examples are the Vd of a drug when its distribution is not Gaussian, and it hardly ever is.
315
You might look at Dodge et al, Population PK Models - Measures of Central Tendency,
Drug Invest 5: 206-211, 1993.
90033
On 21 Oct 97 16:55:09
It seems to me that the data will determine whether you use mean, median or perhaps the
mode to describe the central tendency of the distribution.
For the typical plasma profile, I think that it is often best just to show just the individual's
data. Often presenting the mean, or similar, will hide interesting things in the conc-time
profile such as secondary peaks which may be due to enterohepatic cycling.
For PK population parameters, you should present the information that you have for
them. If you used a computer program that yielded the geometric mean (and CV%) then
this is what you should present. If, however, you used a computer program that yielded
the frequency histogram of the parameters then it would seem appropriate to present the
entire frequency histogram. Presenting only the arithmetic mean and standard deviation
implies that the distribution of the parameter is Gaussian (which would need formal testing). Presenting the median and quartiles (etc) does not describe the distribution very
well. Both parametric and nonparametric descriptions will tend to hide interesting things
in the distribution of the parameters, eg subpopulations of patients that have dierent values (eg genetic polymorphism).
Steve Duull
On 23 Oct 1997 at 09:42:54
NONMEM, because it is an maximum likelihood method, reports the mode for the population parameters. This is one reason that the population estimates do not equate to the
mean or median of the individual estimates.
316
Leon Aarons
M13 9PL, U.K.
On 18 Nov 1997 at 13:41:23
If you want a simple answer to your simple question, it is median. More detailed analysis,
however, is required if the inter-individual variability is extremely large, as in case of polymorphic metabolism. If the distribution of CL is actually bi- or poly-modal you can hardly
find a unique parameter to represent a typical value.
How to do such analysis using minimal modeling assumptions? Suppose (a rather typical
example) you have many individual plasma concentration-time profiles obtained at the
same dosing regimen, and individual sampling times are close to each other. Calculate medians of individual measurements belonging to each sampling time cluster. Then take ratios of measurements to the corresponding medians and plot those ratios versus the individual sequential numbers. You will immediately see the 'outlying' subjects which you have
to analyze separately from others. You may also pool all individual measurements adjusted
for sampling time-specific medians to get idea about the form of overall concentration distribution (unimodal, poly-modal, normal, lognormal, etc.). This simple approach will help
you to select an appropriate way of further summarizing your PK data.
Vladimir Piotrovsky, Ph.D.
Janssen Research Foundation, Clinical Pharmacokinetics, B-2340 Beerse Belgium
317
S EC T I O N 46
Modeling Pharmacokinetic Data

On 7 Jan 1997 at 10:59:41
Hi there, I have two questions about PK modeling

1.
I am doing simultaneous curve fitting for drug concentration-time data in several tissues using compartmental models with PCNonlin. Since drug concentration magnitude is very dierent, say, one tissue concentration is 700 mg/g and another is 0.5 mg/
g. It was suggested to transform the data into dimensionless value to get the concentrations at the same scale or even use the logarithmic transformation to decrease the data
distance. My questions are (1) is there any reference about such data transformation in
PK, (2) how to transform the data into the same magnitude and (3) if I transform the
data by dividing them by their averages, which way I should go, transforming the data
first and then doing the modeling or using the averages as weighting factors-but how
to write the weighting command for the average weighting option.
2. Is there any "tricky" part about fitting infusion data from both infusion and postinfusion periods? I can use following dierential equations to simultaneously fit the
data of both periods. If t>240, then
dz(1)=-kel*z(1)
else
dz(1)=D/(T*V)-kel*z(1)
endif
The problem is I can fit the infusion period well but the results of simultaneous fit
were not satisfying, specially the post-infusion period. Is this problem model-related
or drug disposition dierent between the infusion and post-infusion periods?
Tony Lee
318
On 8 Jan 1997 at 14:09:41
Your problem concerning what you call a large "data distance" is very common in physiological modeling because biological concentrations can range from 1E-2 M down to 1E-15
M or even less. A standard solution to this large dynamic range problem involves using relative weighting instead of absolute weighting of the data to be fitted. I'm not familiar with
the way PCNonlin handles this situation, but I'm quite certain you could solve this problem easily in SAAM II.
I believe you could also reproduce your infusion-postinfusion protocol quite easily in
SAAM II, and all without writing code or having to own a compiler.
Robert D Phair PhD
BioInformatics Services: http://www.webcom.com/rphair
319
S EC T I O N 47
Modeling versus Non-Compartmental

Pharmacokinetic Analysis
On 12 Sep 1997 at 10:26:40
Would anyone in the PK group be able to briefly (or in depth, if appropriate) give some
sort of guidelines as to what are the relative merits of modeling PK data or using noncompartmental PK analysis for obtaining the usual PK parameters eg F, AUC, elimination
rate constant(s), accumulation, clearance etc..
A second but related question is would the answers to above query still hold if the analyses
were extended to include PK/PD.
Faruq H Noormohamed
On 15 Sep 1997 at 15:23:06
The clearest "guideline" to me is that non-compartmental analysis is used to describe PK

parameters and PK modeling is used to describe plasma (or some other matrix) concentrations. Nevertheless, the same parameters obtained via non-compartmental analysis can be
obtained from PK modeling.
Take these examples:
1.
Non-compartmental analysis gives you apparent clearance which allows you to compute mean steady-state concentrations. When done correctly and with appropriate assumptions, PK modeling will allow you to compute the concentration at any time
point following a dose, or multiple doses of a drug.
2. Non-compartmental analysis will give you the Cmax of a drug. PK modeling will give
you Cmax and allow you to compute how long it will take for concentrations to decline to a sub-toxic (or sub-therapeutic) threshold
320
Cases where non-compartmental analysis works best are when a predefined PK hypothesis
(bioequivalence, drug IX, ...) is defined and answered in a well designed study. PK
modeling can be used in these cases too, but its complexity is often not warranted. PK
modeling is very handy when analyzing sparse data, when complicated dosing regimens are
administered, or when extrapolations (new doses, regimens, etc...) are required.
When doing PK/PD modeling, one associates concentrations with eects. Therefore, PK
modeling is usually used, even if only as a "smoothing" function to supply plasma concentrations to the PD model.
Jerey Wald, Ph.D.
Quintiles, Incorporated, Post Oce Box 13979, Research Triangle Park, North Carolina
27709-3979
On 15 Sep 1997 at 15:10:55

Would anyone in the PK group be able to briefly (or in depth, if appropriate) give
some sort of guidelines as to what are the relative merits of modeling PK data or
using non-compartmental PK analysis for obtaining the usual PK parameters eg F, AUC,
elimination rate constant(s), accumulation, clearance etc..
IMHO non-compartmental estimates are convenient ways of *describing* PK expts. They

have uses for those who enjoy stamp collecting and for satisfying regulatory requirements.
However, they are of limited use for *predictive* and *explanatory* purposes. For this, a
physiological/ compartmental model approach is more useful.
A second but related question is would the answers to above query still hold if the
analyses were extended to include PK/PD.
PKPD analyses seem to me illustrate very clearly the severe limitations of the Cmax,Tmax, AUC (elementary) school of pharmacokinetics. It is only by using a model capable of
describing the time course of drug concentrations that any progress can be made in understanding the time course of drug eect in vivo. I prefer physiological / compartmental
models to the black box models which rely on convolution or splines because the parameters of the former classes of models are often closely linked to structure and function and
thus the influence of changes in say body size or blood flow on PK and PD can be predicted.
Nick Holford
321
On 16 Sep 1997 at 13:27:16
I have found it fascinating that Nick Holford and I have come to such similar positions by
such dierent routes. I agree so strongly with Nick's response to this inquiry, that I considered not replying so as not to use up bandwidth with "me too."
But then I saw the post from Hans Bender regarding PK in transgenic animals, and I
thought a combined response to the two inquiries might be useful.
I have been working with a group at the US National Heart Lung and Blood Institute's
Molecular Disease Branch on a kinetic model of lipoprotein metabolism in human LCAT
transgenic rabbits. The principal experimental investigators are Drs. Meg Brousseau and
Je Hoeg and the lab is guided by Dr. Bryan Brewer. An abstract on this work will be presented at the 1997 meeting of the American Heart Association in Orlando in November.
My experience is that analysis of data from transgenic animals is tremendously more informative in the context of a physiological/compartmental model than it could be using noncompartmental methods. This is because, as Nick emphasized, the parameters of a compartmental model are explicitly associated with known or hypothesized physiological processes. This means that a powerful constraint is available to the modeler because he or she
can point to a rate constant or a clearance and say with conviction that *this* process
should be up-regulated in the transgenic animal because this process is mediated by the
gene product of the transgene. Such constraints make it much easier to extract new and
useful information from the available experimental data. There may well be additional control mechanisms that lead to secondary changes in other clearances, but it is really powerful to see if the eect of the transgene alone is sucient to account for the data.
Because the parameters of non-compartmental analysis are combinations of many rate constants or clearances, they can be used eciently to make predictions. But they will not permit you to impose constraints such as the one I allude to above, and they will keep you in
the dark concerning the underlying physiological mechanisms. Biologists think mechanistically, and medicine, as Lewis Thomas has eloquently emphasized, is at its best when based
on mechanism. To build strong working relationships with these two constituencies,
322
mechanistic compartmental models are highly desirable. And while Nick is entirely correct that noncompartmental parameters are all you currently need for the FDA, there are
already well-placed people in the FDA who see the power of compartmental approaches
and the prudent pharmacokineticist should certainly consider adding this approach to his
or her professional toolbox.
Robert D. Phair
On 16 Sep 1997 at 13:28:55
I agree with Nick on the advantages and power of using physiologically based/
compartmental modeling of PK data. There is one significant reason for the development
and success of Non-Compartmental modeling of kinetic data. As the name suggests, there
is no mathematical modeling of the data i.e. no judgements have to be made regarding the
selection of the appropriate number of physiological compartments or exponentials to fit
the data. Additionally, since the mathematical `best' fit of sum of exponential data is based
on statistical parameters such as `goodness of fit', sum of squares, selection of optimal
weighting factors, etc. this interpretation can be subjective and kineticist dependent. I am
sure many kineticists have experienced diculty in modeling oral data which falls through
a 3-4 log orders of magnitude--where in attempting to fit the terminal phase, the profile
around Cmax is not well fit (It is also for this reason the FDA prefers an observed Cmax
rather than a calculated Cmax). Non-Compartmental analysis of the data allows one to estimate most of the basic kinetic parameters for characterizing the disposition of the drug.
Granted that mechanistic interpretation of the kinetic data is limited.
I prefer to use Non-compartmental analysis for basic kinetic interpretations of pilot studies etc. If there is a need for further kinetic evaluation modeling is recommended. I do not
see how Non-Compartmental estimates can be extended to PK-PD modeling since we
have not established the time-course of drug disposition. At best we can make qualitative
(non-predictive) interpretations on the kinetic and dynamic data.
Anup Zutshi
323
On 16 Sep 1997 16:07:35 -0400
In reply to Anup Zutshi:

I am always surprised when people assert that no judgements have to be made with noncompartmental approaches. It appears to me than many of the most common noncompartmental parameters depend critically on the kineticist's judgement as to how to extrapolate the tail of the plasma disappearance curve to infinity. If we guess wrong or miss a
slow exponential because we didn't have data points for enough hours or days, our noncompartmental answers are simply wrong. Moreover, they are wrong precisely because our
judgement was faulty.
We all make errors if we think that there are no assumptions and no calls for judgement in
the application of non-compartmental analysis. If PK did not require judgement, but only
required plugging into published formulas, then the discipline of pharmacokinetics could
be reduced to an algorithm. Non-compartmental analysis has made tremendous contributions to the rational design of therapy, but it is not magic.
The bottom line is that it's impossible to hide from insucient data. Non-compartmental
advocates do the field of PK a disservice by pretending that one method of analysis requires no assumptions or judgement while the other requires both.
On 16 Sep 1997 13:10:43
I would like to second Dr. Holford's description of the strengths and weaknesses on noncompartmental vs physiological / compartmental models. The latter give structure to the
analysis, and result in a controllable system for which one can plan dosage regimens not
just to achieve a desired goal in a steady state situation, but which can grab a patient (if
you will) in an unsteady state and achieve a desired goal then and thereafter, until the
steady state is reached. As far as I know, non-compartmental models are good for writing
papers, but not so good for taking care of real people in unstable and changing clinical
situations. Models having structure are better suited for developing individualized regimens to achieve, and then to maintain, chosen target goals.
324

90033
On 17 Sep 1997 01:28:21
Regarding Faruq Noormohamed's query and the flourish of excellent comments that followed:
In the course of planning our pharmacokinetics analysis software, "PK Solutions", we took
a look at what parameters researchers are publishing and what methods they favor. A survey of all the articles dealing with pharmacokinetics appearing during the last 5 years in
the Drug Metabolism and Disposition and in the Journal of Pharmaceutical Sciences revealed a
>96% use of non-compartmental methods. Most papers included results derived from
both graphic (AUC, etc.) and summed exponential calculations.
Observation: you are in good company with non-compartmental methods.
Summit Research Services, 1374 Hillcrest Drive, Ashland, OH 44805 USA
On 17 Sep 1997 08:59:37
Our article:
Durisova, M., Dedik, L., Balan, M.: Building a structured model of a complex
pharmacokinetic system with time delays, Bu!. Math. Biol., 57, 1995, 787-808,
devoted to non-compartmental modeling, describes in a tutorial manner a procedure
for building a structured model of a complex pharmacokinetic system on using its transfer function. The example employed is that of the pharmacokinetic system based on gentamicin plasma concentrations after intravenous and intra-tracheal administration to
guinea pigs, describing the pathway of the drug into the systemic circulation after
the extravascular injection mentioned. The structured model selected consisted of a
sub-model of a proportional linear subsystem, two sub-models of simple linear dynamic subsystems with time constants of 0.135+-0.065 hr (95 % I.C.) and 0.052+-0.049
325
hr, and two sub-models of parallel subsystems with time delays of 0.254+-0.046 hr and
1.135+-0.288 hr, connected in serial. The serio-parallel structure of the model selected
allowed to estimate mean residence times for four fractions of gentamicin. From the
methodological point of view, our paper demonstrates the eciency of combination of
modeling in the frequency and in the time domain, designed to facilitate studies of complex pharmacokinetic systems.
Diploma Engineer Maria Durisova CSc.,
Scientific Secretary, Institute of Experimental Pharmacology, Slovak Academy of Sciences,
Dubravska cesta 9, 842 16 Bratislava, Slovak Republic
On 17 Sep 1997 22:33:45
Anup,
Thanks for your comments and I think we basically agree but in case there are still some
die hard anti-modeling types left out there...
There is one significant reason for the development and success of Non-Compartmental
modeling of kinetic data. As the name suggests, there is no mathematical modeling of
the data i.e. no judgements have to be made regarding the selection of the appropriate
number of physiological compartments or exponentials to fit the data. Additionally,
since the mathematical `best' fit of sum of exponential data is based on statistical
parameters such as `goodness of fit', sum of squares, selection of optimal weighting
factors, etc. this interpretation can be subjective and kineticist dependent.
The very fact that there is some subjectivity and kineticist dependency is one of the reasons why modeling is valuable. Having to THINK about what you are doing instead of
blindly cranking out Tmax, Cmax, AUC is the way to understand what the data is trying to
say. When the model does not fit an opportunity presents itself to ask why. Indeed models
that fit the data are less interesting in the spirit of scientific enquiry than those that don't.
> I am sure many kineticists have experienced diculty in modeling oral data which falls
through a 3-4 log orders of magnitude--where in attempting to fit the terminal phase, the
profile around Cmax is not well fit
Sure. I recognize the problem. And it has made me more aware of the need to think more
carefully about the processes that govern drug input. The dierence between the necessarily simple prediction of the model and the observed reality is the only way to learn more
about the PK of absorption. Tmax and Cmax are even more naive than the elementary
326
one compartment first-order input, first-order elimination model and will teach you next
to nothing about a drug's absorption rate.
Nick Holford
On 18 Sep 1997 at 10:17:06
Further comments on compartmental versus non-compartmental PK

I have used non-compartmental approach in PK analysis for considerable time and feel
compelled to express my opinion. I certainly agree with the merits of compartmental PK/
PD analysis in understanding mechanism of drug kinetics and dynamics. However, let's
not discard and ridicule non-compartmental approach entirely. One can do very sophisticated PK analysis (with eects of covariance included) using non-compartmental approach. One can even do simulation of concentration time curves using superposition
method.
The greatest advantage of non-compartmental approach is in drug development where
one needs an accurate measure of drug exposure across dierent species. One of the most
powerful non-compartmental PK parameter is AUC(tau) at steady state which allows us to
determine CLss/F as well as drug exposure. This approach requires minimum assumptions
.
In my opinion inaccuracies in the error and structural model in the compartmental PK approach especially with sparse sampling is grossly underestimated and there are times
where I get the feeling that compartmental PK is being reduced to number crunching.
Both compartmental and non-compartmental analysis have their place in pharmacokinetics and serve as useful tools in understanding drug kinetics.
Aziz Karim, PhD
327
On 19 Sep 1997 at 10:26:47
As far as I have seen, the replies on this topic did not deal with the parameters Mean Residence Time (MRT) and Vss in non-compartmental PK analysis. Therefore I would like to
add two notes:
1.
Calculation of MRT and Vss in non-compartmental PK analysis (using AUC and

AUMC) implies the assumption that the rate of elimination from the body is proportional to the (plasma) concentration (equivalent to: elimination from the central compartment in compartmental analysis). If this is not the case (for many drugs, e.g. atracurium which breaks down spontaneously in any body fluid), the values obtained for
MRT and Vss are meaningless. Of course, the same is true in compartmental analysis,
but in that case one is 'forced' to choose a model, including the route of elimination
(do we all realize this every time we use an open two- or three-compartment model
....?).
2. Calculation of MRT and Vss in non-compartmental PK analysis implies calculation of

AUMC (area under the first moment curve). Calculation of AUMC without a curvefitting procedure is prone to large extrapolation errors (much more than AUC!).
In conclusion, be very careful in calculating MRT and Vss by non-compartmental PK analysis!
Johannes H. Proost
On 24 Sep 1997 at 11:01:25
Dear Faruq hi!

Only some observations for your first question:
1.
It's important remember that non-compartmental methods (NCM) ASSUME LINEAR PHARMACOKINETICS for observed drug.
2. NCM are useful to estimate some PK parameters, useful for clinical practice (bioavailability, clearance, apparent volume of distribution, fraction of a dose converted to a
328
metabolite, rates of absorption), but they do not describe the time course of drug in
the blood (dierent half-lives, k-rates, etc)
NCM do not require the assumption of a specific compartmental model for drug and are
based essentially on the theory of statistical methods, and concentration-time course after
single administration can be considered a statistical distribution curve. The results are also
independent enough on changes of metabolism/distribution/elimination during the time.
Compartmental methods required for PK of a drug, depends in part on the experimental
design and you can have problems of accuracy when the frequency and timing of samples
are not correct (too sparse, interrupted too early, etc).
In addition calculation of PK parameters and of distribution rates are dependent on the
model selected, but "many" models sometimes are structurally identifiable and give you
"acceptable" solution. You should therefore perform a robust error-analysis on your data.
Elena Strocchi
Laboratorio di Farmacocinetica ANT, Dipartimento di Chimica Organica, Universita' di
Bologna, Viale Risorgimento, 4, 40136 Bologna - Italy
329
S EC T I O N 48
Nephrotoxicity of Antimicrobials
On 24 Apr 1997 at 11:10:33
I need to know what are the most important parameters of nephrotoxicity to be studied
for a given antimicrobial dug (aminoglycosides, Polymyxin B etc) in animal models (rats).
For how long that drug will be administered (chronic and acute)? and what dosage? etc.
I need this information for toxicological studies.
Abdel Omri
On 28 Apr 1997 at 11:22:05
My lab is presently investigating exacerbation of NSAID-induced renal toxicity by gentamicin and other such peri-operative minefields. We use a rat preparation with several indices of renal toxicity .
1.
Plasma clearances of iothalamate to approximate GFR and paraaminohippurate to approximate renal plasma flow
2. Plasma and urinary electrolytes and osmolality

3.
Histopathology of kidney
No one index is enough. Gentamicin alone can trigger all three indices. Hope that this
helps provide a basis for your further consideration.
Laurie Mather
Professor of Anaesthesia and Analgesia (Research), University of Sydney at Royal North
Shore Hospital, St Leonards NSW 2065 Australia
330
On 5 May 1997 at 14:28:33
I would like to study the nephrotoxicity of an antibiotic but I don't know which are the
most important parameters of nephrotoxicity (creatinine, histopathology of the kidney
etc)
Abdel Omri
On 12 May 1997 at 15:57:15
This is an interesting question. It would appear, that there are a number of proposed methods for measuring the nephrotoxicity of antibiotics. These include NAG, renal proteins,
creatinine, phospholipids and true antibiotic clearance. I have some experience using various markers in an animal model.
Creatinine is an insensitive and slow changing marker. Changes in creatinine change 48 to
72 hours after the renal damage has occurred.
NAG and renal proteins are a bit more sensitive, however can also be disturbed by other
pathology.
Changes in aminoglycoside clearance would appear to be more sensitive than all the above
indices in my animal model. I need to complete the remainder of my experiments to sort
this out. However, anecdotal evidence in humans would also appear to support this.
It would appear that the most sensitive and earliest marker of renal damage is the measurement of phospholipiduria. I have some experience in the measurement of this index of
aminoglycoside induced nephrotoxicity using an animal model.
Carl Kirkpatrick
Department of Clinical Pharmacology, Christchurch Hospital, New Zealand
331
5
1998
332
6
1999
333
AAPS
American Association of Pharmaceuitcal Scientists
http://www.aaps.org/
Related Glossary Terms

Drag related terms here
Index
Find Term
Chapter 1 - 1994
ABW
Actual Body Weight

IBW
AR
Accumulation Ratio

AUC
Area under the curve, especially under the plasma concentration versu
curve

BID
Twice daily dosing

QD
CR
control release

CVVH
Continuous Venovenus Hemofiltration

CVVHD
CVVHD
Continuous Veno-venous Hemodialysis

CVVH
DVT
Deep vein thrombosis
http://en.wikipedia.org/wiki/Deep_vein_thrombosis

EC50
Eective concentration 50%. The concentration which produces a res

equal to half (50%) of the maximum response

HPLC
high pressure (performance) liquid chromatography

IBW
Ideal body weight

ABW
IS
Internal standard

LBM
Lean body mass
Hallynck T, Soep HH, Thomis J, Boelaert J, Daneels R, Fillastre JP, De

Rubinstein E, Hatala M, Spousta J and Dettli L, 1981 Prediction of cre
clearance from serum creatinine concentration based on lean body m
cal Pharmacology and Therapeutics, 30(3), p 414-21.

LMWH
Low molecular weight heparin
http://en.wikipedia.org/wiki/Low_molecular_weight_heparin

LOD
Limit of detection

LOQ
LOQ
Limit of quantitation

LOD
LR
Loo-Reigelman method analysis

WN
PD
Pharmacodynamics

PK
Pharmacokinetics

QD
Daily dosing

BID
SR
Sustained release

SS
Steady state

USP
United States Pharmacopeial Convention
http://www.usp.org/

WN
Wagner-Nelson method of analysis

LR

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PharmPK

David Bourne, Ph.D.

These archives presents the discussions submitted to the

2013 David W.A. Bourne, Ph.D.

Started in November 1994 after discussion at AAPS with

Lag in Urine Clearance - Urine/Plasma

ments in MULTIFORTE. Supplied as compiled programs for Macintosh, MSDOS and

NONMEM (for population simulations).

Neural Net Software

This is by no means complete, but it is a place to start:

Erb RJ 1993 Introduction to backpropagation neural network computation. Pharm Res

4. Veng-Pedersen P and Modi NB 1992 Neural networks in pharmacodynamic modeling.

A few comments regarding neural networks for PK/PD applications:

The delta-backpropagation network should be considered to be a "multiple nonlinear

4. Research is needed for developing indicators or metrics for network performance.

You might take a look at a review on ethanol PK in Clinical Pharmacokinetics 1987;

On 28 Oct 1995 at 21:21:43

Analytical Methods for Moisture

There is a full description in the section of 'Water

The following book has a very good summary on KF method:

Blinding Clinical Studies

On 28 Nov 1995 at 14:04:15

Convolution and Deconvolution techniques to

On 19 Dec 1995 at 13:34:44

For the equal inputs,

Eq.5 can be rewritten in the simple form of Eq.7

On 20 Dec 1995 at 13:52:51

Wagner-Nelson is considered a specialized (read limited ?) form of deconvolution. Limited

On 10 Jan 1996 at 13:09:08

I consider LR and WN as parametric forms of deconvolution. However, I also consider

On 19 Jan 1996 at 11:14:32

where t represents time.

Double Sites Kinetic - Software

Hello to the recipients of the pharmacokinetic List,

Frequency response method

Dedik, L. and M. Durisova 1994 Frequency Response Method in Pharmacokinetics. J.

Durisova, M, Dedik, L, and Balan, M. 1995 Building a structured model of a complex

HPLC Standard Curve

On 11 Dec 1995 at 10:46:11

On 13 Dec 1995 at 14:09:28

Nicotine Patch and Cotinine Measurements

On 24 Aug 1995 17:23:17

We used CO analyzers for our nicotine patch/I.V. studies here at Maine

On 29 Aug 1995 22:41:35

Pharmacokinetics and MathCad

On 4 Dec 1995 at 17:21:37

On 5 Dec 1995 at 11:05:37

PharmPK mailing list recipients:

Phenytoin Dosed by Total or Lean Body

One of the pharmacists asked this tonight...

Several people responded to the query, "Should IV Dilantin be dosed on Lean

Arch. of Neur., 1985, 42, 468-71

Ought not the calculation be:

of phenytoin in obesity: dose weight = IBW [1.33(ABW-IBW)] as proposed in Arch Neur

pKa for ketoconazole

On 3 Nov 1995 at 10:00:36

PKPD Wheal Flare

The pharmacokinetics of propofol are best described by a multicompartmental model.

Rat/Mouse Blood Flow

CLCr = [(140-age)(body mass)]/[SrCr72]