NONCOMPARTMENTAL ANALYSIS
Deficiencies of compartmental analysis:
1. Lack of meaningful physiological basis for derived
parameters.
2. Lack of rigorous criteria to determine # of
compartments necessary to describe disposition.
3. Lack of ability to elucidate organ specific
elimination.
4. Inability to relate derived parameters to quantifiable
physiological parameters.
5. Inability to predict impact of pathophysiology.
6. Inability to provide insight into mechanism of drugdrug and drug-nutrient interactions.
7. Highly sensitive to sampling frequency.
1
GENERAL PRINCIPLES OF
STATISTICAL MOMENTS
MOMENT: A mathematical description of a
discrete distribution.
STATISTICAL MOMENTS:
Utilized in chemical engineering to describe
flow data
First applied to biological systems by Perl
and Samuel in 1969 to describe the kinetics of
cholesterol
Examples of Statistical Moment Usage
In statistics
N
M0
M1
M2
M3
M4
(mean)
i X
2 3/ 2
i X
2 2
(variance)
(skewness)
(kurtosis)
3
In statistics, the mean is a measure of a sample
mean and is actually an estimate of the true
population mean.
In pharmacokinetics, we can calculate the
moment of the theoretical probability density
function (i.e., the solution of a differential
equation describing the plasma concentration
time data),or
we can calculate moments from measured
plasma concentration-time data.
These curves are referred to as sample
moments and are estimates of the true curves.
4
Assume a theoretical relationship of C(t) as a
function of time. The non-normalized
moments, Sr , about the origin are calculated
as:
S r t C (t )dt
r
(r 0,1,2,...m)
Kinetic parameter
C
(
t
)
dt
AUC
Area under the curve
tC (t )dt
AUMC
Area under the moment curve
AUMC Ctdt
0
AUC Cdt
0
ADVANTAGES
widely used to estimate the important pharmacokinetic
parameters.
Ease of derivation of pharmacokinetic parameters by simple
algebraic equations.
The same mathematical treatment can be applied to almost any
drug or metabolite provided they follow first order kinetics.
A detailed description of drug disposition is not required.
DISADVANTAGE
Limited information regarding the plasma drug
concentration time profile,
8
From: Rowland M, Tozer TN.
Clinical Pharmacokinetics
Concepts and Applications,
3rd edition, Williams and
Wilkins, 1995, p. 487.
Kinetic parameter
First moment:
tC (t )dt
0
C (t )dt
AUMC
AUC
MRT
Mean residence time
10
AREA DETERMINATION
A. Integration of Specific Function
Must elucidate the specific function
Influenced by the quality of the fit
Ci
AUC
i
Ci
AUMC 2
i
C1 C2
example : AUC
1 2
C1 C2
example : AUMC 2 2
1 2
11
B. Numerical Integration
1. Linear trapezoidal
2. Log trapezoidal
12
B. Numerical Integration
1. Linear trapezoidal
Area t2 12 (t 2 t1 )(C1 C2 )
Concentration
Time
tn
Area 0 12 (C1 C2 )(t 2 t1 ) 12 (C2 C3 )(t3 t 2 ) ...
12 (Cn 1 Cn )(t n t n 1 )
13
B. Numerical Integration
1. Linear trapezoidal
Advantages: Simple (can calculate by hand)
Disadvantages:
Assumes straight line btwn data points
If curve is steep, error may be large
Under or over estimate depends on whether
curve is ascending of descending
14
15
B. Numerical Integration
1. Linear trapezoidal
2. Log trapezoidal
t2
Area t
(C1 C2 )(t 2 t1 )
ln C1 ln C2
16
B. Numerical Integration
1. Linear trapezoidal
2. Log trapezoidal
Advantages:
Hand calculator
Very accurate for monoexponential
Very accurate in late time
points where interval btwn
points is substantially
increased
t2
Area t
(C1 C2 )(t 2 t1 )
ln C1 ln C2
Disadvantages:
Limited application
May produce large
errors on an ascending
curve, near the peak, or
steeply declining
polyexponential curve
17
B. Numerical Integration
1. Linear trapezoidal
2. Log trapezoidal
3. Extrapolation to infinity
Cn
Cdt
z
tn
AUC t
AUMC t
Cn
Cn
2 t n
z
z
18
Cn
AUC 0 AUC 0
KE
tn
Cn
Cn
AUMC 0 AUMC 0 2 t n
KE
KE
tn
19
AUMC Determination
AUC Determination
Cxt
Area
Time (hr) C (mg/L) Area (mg-hr/L) (mg/L)(hr) (mg-hr2/L)
0
0
2.55
2.00
1.00
1
2.00
2.275
3.39
5.39
3
1.13
3.13
3.50
6.89
5
0.70
1.83
3.01
6.51
7
0.43
1.13
2.00
7.52
10
0.20
0.945
0.45
9.80
18
0.025
0.900
37.11
Total 10.21
t18
AUC 0 10.21 mg hr / L
t18
AUMC 0 37.11 mg hr 2 / L
20
t18
AUC 0 AUC 0
C18
KE
0.025 mg / L
AUC 0 10.21 mg hr / L
0.26 hr 1
AUC 0 10.31 mg hr / L
t18
AUMC 0 AUMC 0
t18C18 C18
2
KE
KE
0.45 mg hr / L 0.025 mg / L
AUMC 0 37.11 mg hr / L
1
1 2
0.26 hr
0.26 hr
AUMC 0 39.21 mg hr 2 / L
21
CLEARANCE CONCEPTS
Q
Ca
ORGAN
Q
Cv
elimination
If Cv < Ca, then it is a clearing organ
22
Rate In = QCa
Rate Out = QCv
Rate of elimination = QCa QCv
= Q(Ca Cv)
23
Q(Ca Cv )
CL QE
Ca
Clearance:
The volume of blood from which all
of the drug would appear to be
removed per unit time.
24
Extraction Ratio:
Ratio of the rate of xenobiotic
elimination and the rate at which
xenobiotic enters the organ.
Rate of Elimination
E
Rate of Entry
Q(Ca Cv ) Ca Cv
E
QCa
Ca
25
Relationship between CL & Q
Since CL = QE, if E~1:
CL
Q
Perfusion rate-limited clearance
26
Total Clearance
Total (systemic) Clearance:
CLT
dX
Elimination rate
dt
C
concentration in blood
27
Total Clearance
Total (systemic) Clearance:
CLT
dX
Elimination rate
dt
C
concentration in blood
Integrating from 0 ,
CLT
dX
0 dt dt
Cdt
, where
0
dX
dt total amt eliminated (Div)
dt
and Cdt AUC
0
Therefore CLT
Div
AUC 0
28
Additivity of clearance
Rate of elimination = Rate of Renal Excretion +
Rate of Hepatic Metabolism
Dividing removal rate by incoming concentration:
Rate of Elimination Rate of Renal Excretion Rate of Hepatic Metabolism
Ca
Ca
Ca
Total Clearance = Renal Clearance + Hepatic Clearance
CLT = CLR + CLH
29
Exception: sig. pulmonary elimination
From: Rowland M, Tozer TN. Clinical
Pharmacokinetics Concepts and
Applications, 3rd edition, Williams and
Wilkins, 1995, p. 12.
30
X
fR
,
Div
CLR CLT f R
100 mg drug administered to a volunteer resulted
in 10 mg excreted in urine unchanged:
X
10 mg
fR
0.1
Div 100 mg
Div
CLR CLT f R
fR
AUC
31
Application of Clearance Concepts
Prediction of the effect of pathophysiological
changes
A new antibiotic has just been introduced
onto the market. Currently, there are no
studies examining the effect of renal disease
on the pharmacokinetics of this compound.
Is dosage adjustment necessary for this drug
when used in pts with renal failure? How can
we gain some insight into this question?
A study in normal volunteers was recently
published and the following data was
included (mean):
32
Application of Clearance Concepts
Prediction of the effect of pathophysiological
changes
CLT = 1.2 L/hr Div = 500 mg
Amount in urine unchanged = 63 mg
X
63 mg
fR
0.126
Div 500 mg
CLR CLT f R
1.2 L / hr 0.126 0.15 L / hr
33
Mechanisms of altered elimination
Verapamil has been shown to elevate
serum digoxin concentrations in patients
receiving both drugs concurrently. A
study by Pedersen et al (Clin Pharmacol
Ther 30:311-316, 1981.) examined this
interaction with the following results.:
CLT CLR
Treatment
Digoxin
3.28 2.18
Dig + verapamil 2.17 1.73
CLNR
1.10
0.44
34
STEADY-STATE VOLUME OF
DISTRIBUTION
VP
Cf
Cf
Cbp
Cbt
VT
35
VP
Cf
Cf
Cbp
Cbt
f up
Cf
CP
CP = Cf + Cbp
f ut
VT
Cf
CT
CT = Cf + Cbt
36
At steady-state:
ASS
VSS
C Pss
CTss
VT
ASS C PssVP CTss VT or VSS VP
C Pss
Substitute:
CTss
Cf
f ut
and C Pss
Cf
f up
37
C f f up
VSS VP
VT
C f
f ut
Simplifying:
f up
VT
VSS VP
f
ut
38
Using blood concentrations:
f ub
VT
VSS VB
f
ut
39
Calculation via moment analysis:
Div AUMC
VSS
2
AUC
Assumptions:
Linear disposition
Administered and eliminated via sampling site
Instantaneous input
40
If administration via a short term
infusion:
2
K 0T ( AUMC ) K 0T
VSS
2
AUC
2 AUC
K0 = infusion rate
T = infusion duration
41
MEAN RESIDENCE/TRANSIT TIME
Administration of a small dose may
represent a large number of molecules:
Dose = 1 mg
MW = 300 daltons
# of molecules = (10-3 g/300) x (6.023 x 1023)
~2 x 1018 molecules
42
Instantaneous administration of the entire
dose will result in xenobiotic molecules
spending various amounts of time in the
body. Evaluation of the time various
molecules spend in the body (residence
time) can be characterized in the same
manner as any statistical distribution.
Mean residence time: The average time the
molecules of a given dose spend in the body.
43
A conceptual understanding can be gained from the
following example: Assume a child received 20 dimes
for his birthday and immediately places them in his
piggy bank. Over the next month, he periodically
removes 1 or more dimes from the piggy bank to
purchase candy. Specifically, 3 days after placing the
coins in his bank he removes 5 dimes, on day 10 he
removes 4 dimes, on day 21 he removes 6 dimes and
on day 30 he removes 5 dimes. At the 30th day after
placing the coins in his bank, all of the coins have
been removed. Hence, the elimination of the deposited
dimes is complete. The MRT of the dimes in the piggy
bank is simply the sum of the times that coins spend
in the bank divided by the number of dimes placed in
the bank.
44
MRT
3 3 3 3 3 10 10 10 10 21 21 21 21 21 21 30 30 30 30 30
20
(3 5) (10 4) (21 6) (30 5)
MRT
20
MRT 16.55 days
45
MRT can be determined for any
given number of drug molecules (Ai)
that spend a given amount of time
(ti) in the body:
n
MRT
At
i 1
i i
Atotal
where n total number of residence times
46
The mean rate of drug leaving the body relative
to the total amount eliminated can be expressed
in terms of concentration:
MRT
tC (t )dt
0
C (t )dt
0
AUMC
MRT
AUC
47
AUMC
MRT
AUC
AUMC po
AUC po
MRT
This is not a definition of MRT,
rather it is a means of
calculating MRT when CL is
constant.
When calculated in this
fashion, it is often said that
MRT is a function of the route
of administration. However,
MRT is independent of the
route.
Meant Transit Time (MTT): The average time for
xenobiotic molecules to leave a kinetic system
after administration.
48
Since an iv bolus assumes instantaneous input:
AUMCiv
MRT MTTiv
AUCiv
AUMC po
AUC po
MTT po
MTT po MTTiv MAT MRT MAT
MAT mean absorption time
49
Vss
MRT
CL
If drug declines via monoexponential decline:
AUMC
MRT
AUC
C0
C0
50
SYSTEMIC AVAILABILITY
AUC po Div
AUCiv D po
51
