NON-COMPARTMENTAL

PHARMACOKINETIC
MODELLING APPROACH

Submitted by:
Rajpreet Kaur
Sandeep Kaur
M. Pharm. Sem.1st

PHARMACOKINETICS
Pharmacokinetics is a discipline of science dealing with the

biological fate of drug and/or its metabolites inside the body

of man or animal during its movement within the body using
mathematical modeling.
Model is a hypothesis based on some sound assumptions to

explain either numerically and/or diagrammatically the fate

of drug inside an animal or human body.
Two important aspects of pharmacokinetic studies are:
Drug analysis
Data analysis

METHODS FOR ANALYSIS OF

PHARMACOKINETIC DATA
MODEL DEPENDENT
APPROACH

MODEL INDEPENDENT
APPROACH

COMPARTMENTAL
MODELLING

NON COMPARTMENTAL
ANALYSIS

MAMILARY MODEL
CATENARY MODEL
PHYSIOLOGICAL
MODEL

PERFUSION LIMITED
MODEL
DIFFUSION LIMITED
MODEL

KEY PITFALLS OF COMPARTMENTAL

ANALYSIS
Lack of rigorous criteria to determine the no. of
compartments necessary to describe the disposition of drug
Highly sensitive to sampling frequency because the no. of

exponentials required to describe disposition depends on

both the timing and frequency of sampling.
Lack of meaningful phsiological basis for derived

parameters.
Model identification and parameter estimation is further

confounded by vanishing exponentials.

Contd
Need statistically sound estimates of each slope and

intercept which sometimes become too complex for

data at hand in multicompartmental analysis.
The same drug in equal doses and administered by

same route may need different model structure in

different patients because model used is one which fits
the data best.
The same drug in equal doses and in the same patient

administered by different routes may need different

model structure to describe their pharmacokinetics.

Contd
So, correct identification of model becomes difficult

as more than one model of comparable complexity is

consistent with the available data.
The basic assumption underlying compartmental

analysis that body consist of few kinetically

homogenous compartments seems to be unrealistic and
difficult to justify from phsiological reality.
Compartmental modelling make use of differing no. of

exponential terms in empirical mathematical

expressions.

Contd
In higher compartmental models, complexity of

mathematical equations makes them difficult to

comprehend.
Difficulty in comparison of pharmacokinetic parameters

within single studies and between studies of same drug.

Possibility of flip flop phenomenon for drugs with shorter

half life following non-instantaneous administration.

Inability to predict the performance of controlled release

drug products.

Contd

Not suitable for extrapolation between species outside

the measured domain as the models are empirical.

Not suitable for Quantitative Structure

Pharmacokinetic Relationship (QSPR) studies.

Tedious drug computation for drugs exhibiting non

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.

NEED TO DEVELOP NON

COMPARTMENTAL METHODS
Due to criticisms of compartmental approach.
To develop a methods of estimating

pharmacokinetic parameters that do not

require tedious and somewhat subjective
method of nonlinear regression.

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

input and data collection.

Other parts of system are not accessible for input and/or data

collection.
This divides the system into accessible and non- accessible pool.
The way in which non-accessible system is described

characterizes the non compartmental model.

All input and all irreversible losses occur from accessible

compartment.

GENERAL MODEL FOR THE

NONCOMPARTMENTAL ANALYSIS
Inaccessible
pool

Input

Accessible
pool

Generalized
Elimination
Sampling

Recirculation

Contd
The fluxes of material in the system that can depart from

the accessible pool before irreversibly leaving the system

are described by recirculation or exchange arrow.
There is no input or loss along recirculation arrow.
Any number of exchanges can occur from any number of

tissues without requiring the identification of any

physiological structures or without the need to assign any
number of compartments or any number of exponentials
to explain the plasma concentration-time data.

Exchange between tissues and

accessible pool
3
2

INPUT

Central
Accessible
pool

ELIMINATIO
N

Contd
The drug follows linear/ first order pharmacokinetics.
Superposition: According to this assumption, when two

inputs are given simultaneously then the resultant response

would be the sum of two separate responses. This principle is
used to determine the response after multiple doses.
Time Invariance: According to this assumption, the response

obtained should be the same from the doses given at different

times e.g. one dose in morning and the other given in the
evening should produce same responses. In other words,
pharmacokinetics of a system does not vary over the time
of data collection.

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

(Recirculation Time), MRTo

TERMINOLOGY
MOMENT: According to Karl Pearson, Moment is a

mathematical description of discrete distribution data. In

pharmacokinetics ,moment is a true estimate of
pharmacokinetic function describing the entire time profile of
plasma drug concentration.

Contd
STATISTICAL MOMENT: is useful in studying the

time related changes in macroscopic events. A

macroscopic events is considered as the over all event
brought about by the constitutive elements involved.
The change in plasma concentration of a drug with
time is a macroscopic events.
MEAN RESIDENCE TIME: This can be defined as

the average time spent by the drug molecule in the

body before being irreversibly eliminated from the
body.

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

MEAN TRANSIT TIME (MTT) :

The average time, that molecules of a given dose spend in
kinetic system. When determined after non-instantaneous
administration , the MTT will be the sum of MRT and MAT.
For I.V. bolus administration MTT=MRT.

MERITS OF STATICTICAL
MOMENT APPROACH
Yields simplistic modeling with fewer, less

restrictive, easily verifiable and realistic

assumptions.
Yields similar pharmacokinetic equations for

drugs thus facilitating comparison.

Can be used to detect nonlinearity in the data.

LIMITATIONS OF STATISTICAL
MOMENT APPROACH
While

computing
non
compartmental
pharmacokinetic parameters following noninstantaneous administration, the knowledge of
parameters following instantaneous route is
obligatory.

When the difference between MRTni and MRTi.v. is

small; it may be difficult to estimate MAT with

adequate accuracy.
25

STATISTICAL MOMENT
THEORY
The concept of statistical moment was first applied in

noncompartmental pharmacokinetics by Yamaoka et al. and Cutler

in 1978.
Statistical moment theory provides a unique way to study time-

related changes in macroscopic events.

A macroscopic event is considered as the overall event brought

about by the constitutive elements involved.

In pharmacokinetics, constitutive elements are the drug molecules

administered into accessible pool and the macroscopic events are

(residence times) exit time shared by group of drug molecules.

Contd
Each drug molecule is mixed well and distributes noninteractively and randomly in the body.

According to the statistical moment theory, the drug molecules in

the body are randomly distributed, and each molecule has a certain
probability to be eliminated at a certain time t.

A mathematical formula describing the probability of a drug

molecule exited at any time is a Probability Density Function

(PDF).

PDF describes the likelihood of exit of drug molecules

(residence time probability of a molecule in a population) to

take place on a given time.

Contd
The probability for the exit of molecules (random variable) to fall within

given time range is given by integral of molecule (variables) density i.e.

C(t) [plasma drug conc.] over the given time range.

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

proportional to plasma drug concentration C(t) so, C(t) is taken as

variables density.(but it may be disadvantage in some cases where
elimination flux is not proportional to C(t).
In this technique zero, first and second moments of statistical distribution

curve are obtained.

In noncompartmental pharmacokinetics, plasma drug concentration-time

curve is considered as statistical distribution curve.

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.

The area under zero moment curve (Conc. Vs time) is termed as

AUC.

The area under curve of a plot of the product of concentration

and time (from zero time to infinity) versus time is often referred
to as the area under the (first) moment curve, AUMC.

Only

zero and first moments are used in pharmacokinetic

analysis because the higher moments are prone to an
unacceptable levels of computational error.

STATISTICAL MOMENTS
In

pharmacokinetics, a moment is true estimate of

pharmacokinetic function describing the entire time profile of
plasma drug concentration (Cp).

Irrespective of route of administration, the first three (zero to

second) moments are:

Eqn.(1)
Eqn.(2)
Eqn.(3)

From equation 1,2&3 AUC, MRT & VRT

can be calculated
Eqn.(4)

Eqn.(5)

Eqn.(6)

GRAPH SHOWING ZERO AND FIRST

STATISTICAL MOMENTS
First
moment
curve
Zero
momen
t
curve
From: Rowland M, Tozer
TN. Clinical
Pharmacokinetics
Concepts and
Applications, 3rd edition,
Williams and Wilkins,
1995, p. 487.

Statistical distribution curve

The time course of drug concentration in plasma
can usually be regarded as a statistical distribution
curve.
The zenith of frequency
curve
() represents MRT.
The square of the horizontal
distance between the
respective bases of the
zenith and the inflection
points () is VRT.

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.

No. of dimes removed

(frequency)

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

Total no. of dimes = 20

Graph Illustrating MRT

In noncompartmental pharmacokinetics, plasma drug conc. C(t) Is taken as

relative frequency and conc. multiplied by time (C*t) is taken as residence time.
Then total residence time (AUC of C*t vs t plot) divided by total frequency
(AUC of C vs t plot)

Contd
So, MRT can be determined for any given number of drug

molecules Ai, which spend a given amount of time in the

body, ti, as follows:

Where n equals the total number of residence times.

The mean rate of drug leaving the body relative to the

total amount eliminated can also be expressed in terms of

concentration as follows:

SIGNIFICANCE OF MRT
Mean Residence Time of drug after intravenous bolus

administration provides a useful estimate of the persistence

time in the body and thus it is related to half life.
MRTi.v. = 1/k & t1/2 = 0.693/k , so as half life tells us about the
time required to eliminate 50% of the dose; here MRTi.v. tells us
about the time required to eliminate 63.2% of the i.v. bolus dose.
Mean Residence Time is a function of how we administer the drug.

MRTn.i. will always be greater than that MRTi.v..

So MRTi.v. can be estimated following other routes of drug

administration as follows:
MRTi.v. = MRTinf (T/2)

For urinary excretion

data

MRT ( Xu Xu )dt Xu
0

Graphically, this represents the ratio of area

beyond the curve ( amount remained to be

excreted) to that of within curve (amount
excreted).

GRAPH PREDICTING URINARY

EXCRETION OF A DRUG

METHODS TO DETERMINE AUC

Methods
Numeric
Non-Numeric
to determine

NON NUMERIC METHODS

1.Graphical method
2.Gravimetric method
3.Planimeter method

NUMERIC METHODS

Linear trapezoidal method

Log trapezoidal method
Cubic spline method
Parabola through the origin
Hybrid method
Lagrange method

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.

accurately along contours

2.GRAPHICAL METHOD: Counting of squares and relating to AUC.

Disadvantages:

Gives only a rough estimate of AUC.

There is a high possibility of human error

PLANIMETER METHOD
A planimeter is a mechanical device that you

can use to compute the area of an irregular figure

after tracing the perimeter of a scale drawing of
the figure with the tracing point on the
planimeter. Calibration is required.
The most commonly used instrument is called
the polar planimeter.

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

of curve, or the lack there of, between data points.

Greater the time interval, greater would be the error.

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

and more suitable for further data analysis.

Disadvantage:
Has large excess variance.

PARABOLA THROUGH THE

ORIGIN METHOD
Here,
g= a+bt+ct2+dt3 (Cubic polynomial) for intervals 2 to n-2
g= a+bt+ct2 (Quadratic) for intervals 1 to n-1
Advantages:
Simple to compute (as compared to Spline Method)
Less biased.
Gives better approx. than a single straight line in middle

intervals.
Disadvantage:
Has large excess variance.

Contd..
Applied for non-instantaneous or extra vascular route only

because in vascular routes there is a definite intercept.

HYBRID METHOD
Trapezoidal and Log Trapezoidal: In this up to

ascending curve linear trapezoidal method is

applied and then to descending curve log
trapezoidal method is applied.
Spline and Log Trapezoidal: In this up to

ascending curve linear spline method is applied

and then to descending curve log trapezoidal
method is applied.

METHODS TO DETERMINE
AUMC
1.
2.
3.
4.
5.
6.

Linear Trapezoidal Method

Log Trapezoidal Method
Lagrange Method
Hybrid Method
Parabola Through The Origin
Spline Method

EXTRAPOLATION OF AUC:
It is quite unpractical to determine areas under curve and moment

curves till infinity. Hence extrapolation is advisable from the last

sampling time upwards till infinity as per the following
relationships:

AUC AUCt * AUCt *

AUMC AUMCt * AUMCt *

AUCt * C * /
AUMCt * C *t * / C * / 2

t* is the last sampling time

C* represents the last sampled plasma concentration
is the slope of the terminal linear portion of log Cp versus time curve

COMPUTATION OF PHARMACOKINETIC
PARAMETERS

Clearance:

Cl= Dose/AUC

Mean Residence Time:

MRT= AUMC/AUC

Apparent Volume of distribution at steady state after i.v.

bolus administration is calculated as follows:

Contd
Relation between MRT and elimination rate constant,k following

i.v. bolus administration for drugs that distribute rapidly:

MRTi.v. = 1/k

For drugs which distributes slowly, MRT is a related as:

MRTi.v. = 1/k

Where k is a rate constant equal to the ratio of Clearance to Vss.

After

i.v. infusion Mean Residence Time is calculated as follows:

MRTinf = MRTi.v. + (T/2) or
MRTi.v. = MRTinf - (T/2)

Where T is the duration of infusion

Contd
Apparent volume of distribution at steady state following

constant rate i.v. infusion

Since the infused dose is equal to k0T then above equation

can be expressed as:

Contd
Mean Residence Time following constant rate i.v. infusion

Where, AUMC/AUC = MRTi.v.

Absorption rate constant ka:

Contd
Steady state concentration:

Steady state concentration is a function of noncompartmental

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)

Calculation of MAT,MIT and MDT

MAT( Mean absorbance time): [Following non-

instantaneous route].
MAT = MRT n.i. MRT i.v.

MIT( Mean input time): [ Following i.v. infusion].

MIT = MRT inf. MRT i.v.

MDT (Mean dissolution time):

MDT = MAT solid MAT solution

MDT and

MAT can eventually be used for

investigating the in-vitro-in-vivo correlations.

The Mean Absorption Time (MAT)

MAT( Mean absorbance time): [Following noninstantaneous route].
MAT = MRT n.i. MRT i.v.
Technically, MAT is really the mean arrival time; that is, the
average time it takes for drug molecules to enter a kinetic space
(such as the systemic circulation).
The most common condition under which MAT is determined is
after administration through non-instantaneous route, many (perhaps
most) authors of texts and journal articles refer to it as the mean
absorption time.
If it is viewed as absorption time, one is considering the time drug
molecules spend at the site of absorption. The problem with this
notion is that rarely is this measured. Instead what is measured is
the appearance of drug in the systemic circulation

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.

CUT OFF ERROR

The risk of error in moment analysis increases with the

magnitude of extrapolation required.

For a case of 1CBM,with oral first order absorption the

potential cut off errors are indicated in the following table:

Percent of
C last / C max

Potential Errors in Parameters

AUC

MRT

VRT

5%

< 5%

<10%

<40%

1%

<1%

<2%

<10%

Software reports on noncompartmental pharmacokinetic

data analysis using statistical approach
Applications

Author(s)

Software

Language

MODMOMT

---

Method for statistical moments

LAGRAN

Examination of AUC and moments using Rocci & Jusko

Lagrange, linear, log- trapezoidal or
combination methods

1983

Pharmacokinetic analysis based on the Reitberg et al

statistical moments

1985

MOM

Calculation of statistical moments in Efthymiopoulos

pharmacokinetic studies

1989

MIND

Evaluation of pharmacokinetic parameters Agafonov & Piotrovskii

by the model-independent method of
statistical moments

1991

NCOMP

FORTRAN

Windows-based
noncompartmental Laub & Gallo
pharmacokinetic analysis

1996

PK-MOMENT

MS-Excel

Spreadsheet package for pharmacokinetic Sato et al.

analysis through stochastic approach

1996

STOCHA

FORTRAN

Computation of AUC and moments using Singh & Ahuja

linear, log-trapezoidal, spline
and
Lagrange methods

1999

Chan & Wnuck

Year
1983

Linear system approach

Applies general linear principles like deconvolution and
convolution.
It describes the entire time course of drug concentration in body in
more comprehensive and dynamic manner.
Approach can be used for:
Prediction or simulation of systemic drug concentration by
convolution.
Estimation of time course of drug absorption by deconvolution.
Establishing in vitro- in vivo correlations.

Recirculatory models
Tend to describe drug disposition in terms of
repeated cycles through the body circulatory
systems.

Sometimes argued to be better than even so

called physiologically based compartmental models.