Non Compartmental Pharmacokinetics
Non Compartmental Pharmacokinetics
Non Compartmental Pharmacokinetics
PHARMACOKINETIC
MODELLING APPROACH
Submitted by:
Rajpreet Kaur
Sandeep Kaur
M. Pharm. Sem.1st
PHARMACOKINETICS
Pharmacokinetics is a discipline of science dealing with the
MODEL INDEPENDENT
APPROACH
COMPARTMENTAL
MODELLING
NON COMPARTMENTAL
ANALYSIS
MAMILARY MODEL
CATENARY MODEL
PHYSIOLOGICAL
MODEL
PERFUSION LIMITED
MODEL
DIFFUSION LIMITED
MODEL
parameters.
Model identification and parameter estimation is further
Contd
Need statistically sound estimates of each slope and
Contd
So, correct identification of model becomes difficult
Contd
In higher compartmental models, complexity of
drug products.
Contd
linear pharmacokinetics.
Calculated pharmacokinetic parameters are highly
model dependent.
ADVANTAGES OF NONCOMPARTMENTAL
ANALYSIS
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.
Pharmacokinetic comparison within studies and between
study is easier as same mathematical treatment is applied to
all data sets, and thus, it is specially useful in bioequivalence
studies.
Contd
A detailed description of drug disposition
characteristics is not required.
Easy detection of nonlinearity.
Timing of sample is not as critical as in
compartmental model analysis.
NONCOMPARTMENTAL
MODELLING APPROACH
Non compartmental
modeling approach
provides a means of
obtaining primary
pharmacokinetic par
ameters of drug with
ou t
using nonlinear regre
ssion and postulating
unrealistic assumptio
ns inherent to
compartmental analy
sis.
BASIC ASSUMPTIONS:
System contains at least one accessible pool that is available for
collection.
This divides the system into accessible and non- accessible pool.
The way in which non-accessible system is described
compartment.
Input
Accessible
pool
Generalized
Elimination
Sampling
Recirculation
Contd
The fluxes of material in the system that can depart from
INPUT
Central
Accessible
pool
ELIMINATIO
N
Contd
The drug follows linear/ first order pharmacokinetics.
Superposition: According to this assumption, when two
NON COMPARTMENTAL
METHODS
Statistical moment approach
Linear system analysis(LSA)
The recirculatory model
NON COMPARTMENTAL
PARAMETERS
Accessible pool parameters:
Volume of Distribution, V
Clearance Rate, CL
Elimination Rate Constant, k
Mean Residence Time, MRT
System parameters:
Total equivalent Volume of Distribution, Vtot
System Mean Residence Time, MRTs
Mean Residence Time Outside the Accessible pool
TERMINOLOGY
MOMENT: According to Karl Pearson, Moment is a
Contd
STATISTICAL MOMENT: is useful in studying the
Contd
MEAN ABSORPTION TIME: Technically, MAT is the
mean arrival time; that is, the average time it takes for
drug molecules to enter a kinetic space (such as the
systemic circulation). However, since the most common
condition under which MAT is determined is after oral
administration, commonly refer to it as the mean
absorption time, which is the time drug molecules spend
at the site of absorption.
Contd
MERITS OF STATICTICAL
MOMENT APPROACH
Yields simplistic modeling with fewer, less
LIMITATIONS OF STATISTICAL
MOMENT APPROACH
While
computing
non
compartmental
pharmacokinetic parameters following noninstantaneous administration, the knowledge of
parameters following instantaneous route is
obligatory.
STATISTICAL MOMENT
THEORY
The concept of statistical moment was first applied in
Contd
Each drug molecule is mixed well and distributes noninteractively and randomly in the body.
Contd
The probability for the exit of molecules (random variable) to fall within
C(t) in general written as f(t) which is actually elimination flux (kXo) here.
Because in first order rate process elimination flux is considered
Contd
AUC, MRT (Mean residence time) and VRT(Variance of mean
residence time of drug in body) are termed the zero, first and
second moment, respectively, of drug concentration-time curve.
AUC.
Only
STATISTICAL MOMENTS
In
Eqn.(1)
Eqn.(2)
Eqn.(3)
Eqn.(5)
Eqn.(6)
Concept of MRT
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.
34
Contd
S.no.
Day of removal
after placing
Residence time
(time spent by
the coins in the
piggy bank)
3+3+3+3+3 or (3*5)
=15
10
10+10+10+10 or (10*4)= 40
21
21+21+21+21+21+21 or
(21*6) = 126
30
30+30+30+30+30 or (30*5) =
150
Contd
So, MRT can be determined for any given number of drug
SIGNIFICANCE OF MRT
Mean Residence Time of drug after intravenous bolus
administration as follows:
MRTi.v. = MRTinf (T/2)
MRT ( Xu Xu )dt Xu
0
NUMERIC METHODS
NON-NUMERIC METHODS
1.GRAVIMETRIC METHOD: Calibrating for weight of curve
versus AUC
Disadvantages
1. Time consuming.
2. Erroneous results if cutting not done
and if paper is not of uniform thickness.
PLANIMETER METHOD
A planimeter is a mechanical device that you
PLANIMETER
NUMER
IC
METHO
DS
NUMERIC METHODS
(I). LINEAR TRAPEZOIDAL METHOD:For a given
time interval (t1 t2), the AUC can be calculated as
follows:
Contd
Advantages:
Simplicity in concept.
Disadvantages:
Linear intrapolation between data points will tend to
underestimate the area when the data form a convex
curve and to overestimate when the curve is concave.
Magnitude of error depend on the oscillatory nature
Contd
(II) LOG TRAPEZOIDAL METHOD:This method is
more accurate when concentrations are decreasing
because drug elimination is exponential (which makes it
linear on a logarithmic scale).
For a given time interval (t1 t2), the AUC can be
calculated as follows:
Contd
Advantages:
Most appropriate when applied to data which appear to decline
exponentially.
Error produced is independent of the time interval.
Accuracy is good as Root Mean Square Error (RMSE) is small.
Disadvantages:
Produce large errors when in an ascending curve, near a peak,
or in a steep descending poly-exponential curve.
SPLINE METHOD
For cubic spline method:
Where,
h= ti+1-ti
Contd
Advantages:
Complete smoothness of the fitted curve (as compared to
Lagrange Method).
Close to reality.
Small algorithmic error so area calculated less distorted
Disadvantage:
Has large excess variance.
intervals.
Disadvantage:
Has large excess variance.
Contd..
Applied for non-instantaneous or extra vascular route only
HYBRID METHOD
Trapezoidal and Log Trapezoidal: In this up to
METHODS TO DETERMINE
AUMC
1.
2.
3.
4.
5.
6.
EXTRAPOLATION OF AUC:
It is quite unpractical to determine areas under curve and moment
AUCt * C * /
AUMCt * C *t * / C * / 2
COMPUTATION OF PHARMACOKINETIC
PARAMETERS
Clearance:
Cl= Dose/AUC
MRT= AUMC/AUC
Contd
Relation between MRT and elimination rate constant,k following
After
Contd
Apparent volume of distribution at steady state following
Contd
Mean Residence Time following constant rate i.v. infusion
Contd
Steady state concentration:
parameters as follows:
Css=k0/Cl
Mean Absorption Time following zero order input:
MAT=(T/2)
Absorption half life is given by:
t1/2 = 0.0693(MAT)
instantaneous route].
MAT = MRT n.i. MRT i.v.
STOCHASTIC
APPROACH
Stochastic approach
Pharmacokinetically, the moment of individual
drug
molecules through body compartment is
governed by probability.
As illustrated, some may hit the target (Stocha)
as all may not get absorbed (or metabolized or
distributed or excreted) and rest may form a
random scatter around a general cluster.
The analysis of statistical moments is, in fact,
the analysis of the probability distribution resulting
as a consequence of the stochastic process.
Percent of
C last / C max
MRT
VRT
5%
< 5%
<10%
<40%
1%
<1%
<2%
<10%
Author(s)
Software
Language
MODMOMT
---
LAGRAN
1983
1985
MOM
1989
MIND
1991
NCOMP
FORTRAN
Windows-based
noncompartmental Laub & Gallo
pharmacokinetic analysis
1996
PK-MOMENT
MS-Excel
1996
STOCHA
FORTRAN
1999
Year
1983
Recirculatory models
Tend to describe drug disposition in terms of
repeated cycles through the body circulatory
systems.