Veterikaty Research Communications, 13 (1989) 141-157

Copyright 0 Kluwer Academic Publishers bv - Printed in the Netherlands

CURRENT MODELS IN PHARMACOKINETICS: APPLICATIONS

IN VETERINARY PHARMACOLOGY

L.D.B. IUNABO AND QA. McKEZLLAR

Department of Veterinary Pharmacology, University of Glasgow Veterinary School,
Bearsden Road, Bearsden, Glasgow, G61 lQH, UK

ABSTRACT

Kinabo, L.D.B. and McKellar, QA. 1989. Current models in pharmacokinetics: applications in veterinary
pharmacology. Veterinary Research Communications, 13 (2), 141-157

Major advances in developing models for pharmacokinetic studies have been made in recent years,
and different approaches can now be employed. These include the use of (1) compartmental models,
(2) non-compartmental models, (3) physiological models, (4) population pharmacokinetic models,
and (5) pharmacokinetic-pharmacodynamic models.
Each of these approaches has both advantages and disadvantages. The important question of
which of these is ideal in veterinary pharmacokinetics has no simple answer. The selection and
application of any one approach would depend on a number of factors, such as (1) the purpose of the
study, (2) physicochemical properties and actions of the drug, (3) specificity and sensitivity of the
analytical methodology, (4) species of the animal, and (5) availability of funds.
This paper reviews the models available for pharmacokinetic studies and indicates their possible
application in veterinary pharmacology.

Keywords: models, pharmacokinetics

INTRODUCTION

The idea underlying the use of models in kinetic data analysis is to obtain parameter
estimates that can be employed for interpolation or extrapolation. Dosing regimens
can thus be tailored according to the physiological or pathological status of an
individual animal and, regarding the use of drugs in food-producing animals, with-
drawal periods can be estimated on a rational basis.
A model is generally defined as a concept, a formula or a drawing. Two types of
models are normally distinguished, namely, models of data and models of systems
(DiStefano and Landaw, 1984). The latter are the most commonly used in kinetic data
analysis.
In the pharmacokinetic literature, confusion exists particularly with regard to the
calculation of parameters (Notari, 1975), the description of models (DiStefano and
Landaw, 1984) and the interpretation of results. Lack of uniformity in the use of
symbols is also evident, particularly in the veterinary literature (Hanna er al., 1988;
Knoppert et al., 1988; Riond and Riviere, 1988; Sanders et al., 1988; Soback, 1988).
Undoubtedly this makes interpretation of the literature difficult. Thorough knowledge
concerning the usage and limitation of kinetic models is essential if any valid
interpretations are to be made from a kinetic study, and the use and abuse of such
models have been reviewed recently (Rescigno and Beck, 1987).
Veterinary pharmacology is an applied science, and inevitably investigators in this
142

field have generally utilized kinetic models rather than developed them. Currently,
approximately 90% of the studies on drug kinetics reported in veterinary journals are
based on the classical compartmental models. This contrasts with the situation in
human pharmacology where non-compartmental analysis and other novel approaches
are increasingly being employed. These approaches are of growing importance not
only in characterizing drug disposition and concentration-activity relationships for
therapeutic purposes, but also in regulating safety levels of chemicals in industrial
environments and in animal products destined for human consumption.
In this review we outline the various models which are currently used in
pharmacokinetic studies and discuss their applications in veterinary pharmacology.
Details of mathematical derivations and proofs of models are beyond the scope of this
article; instead, where appropriate, original and relevant references are given. All the
symbols used for the kinetic parameters in this review are those proposed by Rowland
and Tucker (1980) and adopted as the preferred symbols for use in articles published
in the Journal of Pharmacokinetics and Biopharmaceutics.

COMPARTMENTAL MODELS

In compartmental modeling, the body is represented by a finite number of

components referred to as compartments. The fundamental assumptions that underly
compartmental models in kinetic data analysis are: (1) the drug is homogeneously
distributed in a compartment; (2) organs or tissues with similar kinetic characteristics
may be amalgamated; and (3) drug disposition in the body occurs by first-order
processes. A compartment is described as open if it leaks to the environment, or
closed if it does not (DiStefano and Landaw, 1984). In pharmacokinetics, most models
employed have at least one compartment open with first-order elimination.

One-compartment open model with first-order elimination

In this model, the body is conceived as a single homogeneous system in which a drug
can distribute instantaneously following intravenous administration. Since drug
disposition in the body is assumed to be a first-order process, the process is expressed
by a differential equation of the form:
dA
-= -lG4
dt
where A is the amount of drug in the body at time t, and k is the apparent first-order
elimination rate constant. Integration of the equation and conversion to a
concentration-time relationship yields the expression:

C = C(O)exp(-kt)

where C is the plasma concentration at time t, and C(0) is the plasma concentration at
time zero. A plot of 1ogC versus time gives a straight line with slope equal to -k/2.303
from which k can readily be determined. The elimination half-life (t1,2) is also easily
determined from the graph (Baggot, 1977; Gibaldi and Perrier, 1982).
 143

Multicompartmental models

In this approach, the body is depicted as a system consisting of two or more

compartments interconnected so that drug movement can occur among some or all of
them. The two-compartment and three-compartment open models are the most
commonly used multicompartmental models in veterinary pharmacokinetics.

Two-compartment open model: Three types of the two-compartment open model can
be distinguished depending on which compartment or how many compartments are
open (Figure 1). These models are mathematically similar on the basis of their plasma
concentration-time data or urinary excretion data (Gibaldi and Perrier, 1982).
However, it is usually assumed that elimination takes place solely from the central
compartment because the principal organs of elimination are the liver and kidney
which are both considered to be kinetically equivalent to blood. The peripheral
compartment represents all the other body tissues which are assumed to exhibit
similar kinetic characteristics. The exponential equation used to describe the two-
compartment open model if the drug is given intravenously is:
C = Alexp(-AIt) + A2exp(-X2t)
where C is the plasma concentration at time f, A, and A, are coefficient constants and
A, and X2 are distribution and elimination rate constants respectively (Baggot, 1977;
Gibaldi and Perrier, 1982).

Dose
+-p&r,
I
Elimination
k10

Figure 1. Three types of the two-compartment open model: (1) central compartment,
(2) peripheral compartment. !I2 and k,, are first-order rate constants for distribution;
k,, is the rate constant for ehmination from the central compartment; and k, is the
rate constant for elimination from the peripheral compartment.
144

Three-compartnzent open model: Seven types of the three-compartment open model

can be distinguished, depending on which and how many compartments are open. As
with the two-compartment open model, elimination is also assumed to occur
exclusively from the central compartment. On the basis of the topology of the
compartmental units, two types of three-compartment model are usually distin-
guished. If the compartments are arranged such that the central compartment is
surrounded by and connected with peripheral pools none of which is connected to
another, the model is described as mamillary (Figure 2), but if all the pools are in a
chain, with each pool connected (in series) only to its nearest neighbours then the
model is termed a caternary model (Figure 2). In contrast to the two-compartment
open model, the peripheral system in the three-compartment open model comprises
two pools, a shallow compartment (2) and a deep compartment (3) (Figure 2). The
three-compartment open model for intravenous data is described by a sum of three
exponential terms:
C = A1exp(-X+) + A2exp(-X2t) t A3exp(-X3t)
where C is the plasma concentration at time t; A,, A, and A, are coefficient constants;
X1 and X2 are rate constants for distribution, and X3 is the rate constant for
elimination (Baggot, 1977; Gibaldi and Perrier, 1982).

Dose

Figure 2. Two types of the three-compartment open model: (a) mamillary model; (b)
caternary model

Applications

Although it is normally stated that the choice of compartment model is based on

curve fitting of the plasma concentration-time profile with a single or multiexpon-
ential equation, in which the number of compartments in the model is equal to the
number of exponents in the equation, this is not necessarily true, because many data
that do not come from compartmental systems can be fitted by sum of exponentials
(Rescigno and Beck, 1987). Wagner (1976) has shown that several different compart-
mental models may be expressed by the same number of exponential terms, and
 145

according to Rescigno and Beck (1987) the goodness of fit by any criterion is not in
itself a basis for judgement of which model is best. It is also accepted that a
two-compartment open model following extravascular administration, which must
involve an absorption phase, is adequately represented by a triexponential expression
of the form:

C = A,exp(-X,t) + K2exp(-X.+) - (Ar + AJexp(-kar)

where ka is the first-order rate constant for absorption, and X, and X, are as defined
above. The coefficient constants A, and A, are not the same as defined above
because they are influenced by the rate and extent of absorption (Baggot, 1977).
Although compartmental models have been used extensively in veterinary
pharmacology, fitting experimental data to such models is not always simple (Sedman
and Wagner, 1976; Pedersen, 1977; Bialer, 1980; Landaw and DiStefano, 1984;
Dunne, 1986; Wijnand, 1988). In some cases, investigators have obtained data which
do not lit any of these compartmental models (Chay et al., 1982; Ziv et al., 1982;
Semrad et al., 1985; Ziv et al., 1986; Kinabo and Bogan, 1988b). Table I highlights
some of the limitations of compartmental models. It is evident that several factors
may influence the choice of a model and it seems that inter-individual animal
variability, route of drug administration, drug formulation and physicochemical
properties of the drug may be considered as the most important. Other factors
include frequency and duration of blood or plasma sampling, sensitivity of the assay of
the drug in blood or plasma and weighting of data (Chennavasin et al., 1981;
DArgenio, 1981; Baggot, 1983; Semrad ef al., 1985). These factors can be classified as
physiological, drug-related and methodological, and all demonstrate how compart-
mental analysis is prone to interference that can make comparison of results from
different studies difficult.
The problem of identifiability is also inherent in compartmental analysis. If a
two-compartment model is required to describe plasma concentration-time data,
identification of one of the three potential two-compartment models is necessary to
predict concentrations in the peripheral compartment (Colburn, 1987). This problem
of identifiability also applies to the three-compartment open model. Vaughan and
Hope (1979) have advocated the abandonment of physiologically unrealistic
compartmental models, since other alternative approaches to kinetic data analysis are
available.

NON-COMPARTMENTAL MODELS

Use of non-compartmental models is based on the statistical moments theory

(Yamoka er al., 1978; Cutler, 1978) which has been reviewed recently (Nuesch, 1984;
Beal, 1987). Non-compartmental analysis has been called a model independent
approach by many authors, but this term is considered inappropriate (DiStefano,
1982; Cobelli and Toffolo, 1984) because this method is based on a model with
restricted structure and realm of applicability (DiStefano, 1982; DiStefano and
Landaw, 1984). The main advantages of this approach are, firstly, that none of the
non-central pools are identified with any anatomical structures (DiStefano, 1982)
and, secondly, mathematical analyses of time-varying kinetic data can be accomp-
TABLE I
Compartmental analysis of kinetic data on some veterinary drugs administered as single doses to various domestic animals

Number of animals
according to
compartment model
Animal
rug species Route I-C 2-c 3-c References

Plorfenicol Cattle (n =5) i.v. 1 4 Bretzlaff et al., 1987

Plunixin (0.10 mg/kg) Horses (n = 5) iv. 3 2 Semrad et al., 1985
PIunixin (0.25 mg/kg) Horses (n = S) i.v. 5 Semrad et al., 1985
Sulphatroxazole Goats (n = 6) i.v. 1 5 Kinabo and Nielsen, 1986
Thiamylal Cats (n =6) i.v. 1 5 Wertz et al., 1988
Bumetanide Horses (n =S) i.v. 5 Delbeke et al., 1986
Bumetanide Horses (n = 5) i.m. 5 Delbeke et al., 1986
Phenylbutazone Cattle (n =6) i.v. 6 Lees et al., 1988
Phenylbutazone Cattle (n =6) i.m. 6 Lees et al., 1988
Phenylbutazone Cattle (n = 6) oral 6 Lees et al., 1988
Sulphaphenazole Cattle (n =4) i.v. 4 Odegaard and Rastaad, 1987
Sulphaphenazole Cattle (n =4) oral 4 Odegaard and Rastaad, 1987
Colistin Cattle (n = 6) iv. 0 0 Ziv et al., 1982
Polymyxin B Cattle (n =5) iv. 0 0 Ziv et al., 1982
Plumequine
Injectable solution Cattle (n = 7) i.v. 7 Ziv et al., 1986
Injectable solution Cattle (n =5) i.m. 5 Ziv et al., 1986
Flumacol Cattle (n =26) i.m. 0 0 Ziv et al., 1986
Imaquyl injectable suspension Cattle (n =26) i.m. 0 0 Ziv et al., 1986
Imaquyl water soluble powder Cattle (n =32) oral 0 0 Ziv et al., 1986
Isometamidium Cattle (n =7) i.m. 0 0 Kinabo and Bogan, 1988b

1-C One-compartment open model

2-C Two-compartment open model
3-C Three-compartment open model
 147

lished with integral equations rather than differential equations, in contrast to

multicompartmental analysis (DiStefano, 1982, DiStefano and Landaw, 1984). This is
less demanding from a computational point of view (Cobelli and Toffolo, 1984).
Non-compartmental methods can be employed to derive from kinetic data various
parameters such as: (1) area under the plasma concentration-time curve (AUC); (2)
area under the moment curve (AUMC); (3) mean residence time (MRT); (4)
variance residence time (VRT); (5) mean absorption time (MAT); (6) volume of
distribution at steady state (V3; and (7) total plasma clearance (CL) (Cutler, 1978;
Yamaoka et al., 1978; Benet and Galeazzi, 1979; Riegelman and Collier, 1980). The
formulae for these parameters are presented in Table II. The mean residence time is
defined as the mean time for the intact drug molecules to transit through the body
and involves all kinetic processes including in vivo release from the dosage form,
absorption and disposition (Riegelman and Collier, 1980). The mean absorption time
refers to the mean time involved in the in viva release and absorption processes as
they occur in the input compartment.

TABLE II
Pharmacokinetic parameters which can be derived by non-compartmental analysis

Parameter Formula Units

AUC AIt mass x time/volume

s 0

AUMC tat mass x time2/volume

f
MRT AUMC,AUC time

VRT (I - MRT)C&/AUC time

s0
0.693 x MRT(i.v.) or 0.693/X, time
f&XT MRT(n.i.) - MRT(i.v.) time
Ys CLxMRT volume
CL D(i.v.)/AUC(i.v.) volume/time
F [D(i.v.) xAUC(oral)/D(oral) xAUC(i.v.)]x 100 percent
C max mass/volume
t max time

The non-compartmental approach is rapidly replacing compartmental analysis

(Gibaldi and Perrier, 1982), at least in human pharmacology. In veterinary pharma-
cology, non-compartmental analysis has not yet received much attention. However, it
has been used in some cases, for example to evaluate the pharmacokinetics of
diminazene in sheep (Aliu and Odegaard, 1985), theophylline in goats (Davis et al.,
1987) and dogs (Koritz et al., 1986), flunixin in horses (Semrad et al., 1985),
148

ceftriaxone in cattle (Soback and Ziv, 1988), gentamicin in cats (Jernigan et al.,
1988b), chloramphenicol in cattle (Sanders et al., 1988), cefoxitin in cattle (Soback,
1988) and yohimbine in steers, horses and dogs (Jernigan er al., 1988a). Semrad et al.
(1985) used this approach because compartmental models could not be fitted to the
experimental data on flunixin in horses.
In comparing some parameter estimates derived by compartmental and non-
compartmental analyses, certain criteria need to be fulfilled if erroneous conclusions
are to be avoided. For example, the mean total residence time recovered from non-
compartmental analysis, MRT, is equivalent to the mean total residence time
recovered via compartmental analysis, MRT*, only if the irreversible losses in the
system occur in the accessible compartment, otherwise the true mean residence time
is underestimated (Cobelli and Toffolo, 1984). It should also be noted that in
calculating certain parameters such as MRT and CL, it is assumed that the drug
exhibits linear disposition processes (Gibaldi and Perrier, 1982; Benet, 1985). These
points probably explain the significant differences found for the volume of distribution
of flunixin in horses where the compartmentally and non-compartmentally derived
values were compared (Semrad et al., 1985). Soback (1988) did not find any significant
difference between kinetic parameters for cefoxitin in calves calculated by a
compartmental approach and those obtained by non-compartmental analysis.
Non-compartmental analysis has been considered as an elegant and attractive
approach to pharmacokinetics, which in some way may be seen as an appealing
alternative to compartmental models (Cobelli and Toffolo, 1984). From Table II, it is
clear that the information derived by this approach is adequate for registration of a
drug and also for formulation of dosing regimens (Gibaldi and Perrier, 1982; Segre,
1984).

PHYSIOLOGICAL PHARMACOKINETIC MODELS

The fundamental concept in this approach is the use of parameters which have
structural and functional connotations to characterize drug disposition in the body.
Thus, the model is essentially made up of a sum of differential equations based on
anatomical, physiological and biochemical data. Unlike the classical compartmental
models, physiological models provide greater insights into the dynamics of drug
distribution since they allow a precise description of the time course of drug
concentration in any organ or tissue (Mintun et al., 1980; Gerlowski and Jain, 1983).
In addition, they permit better predictions in cases of pathological alterations and in
extrapolating data from one animal species to another species, that is, animal
scale-up. However, the large amount of data required makes this model difficult to
develop.
Although the first report on physiological models was published some 50 years ago
(Teorell, 1937), there were no extensive developments and applications until the 1960s
and 1970s. The general procedures which are currently used in developing
physiological models have been described in detail in the literature (Gibaldi and
Perrier, 1982; Gerlowski and Jain, 1983; Rowland, 1984). The primary feature
common to such models is the compartmentalization of tissues or fluids on the basis
of kinetic similarity. The number of compartments varies, and may range from 4-10
(Himmelstein and Lutz, 1979). They are all interconnected as depicted in Figure 3.
 149

Inlramuecular
dare

I
Plarma Injeciion alto

It

- Liver

Bile

Heart -

Figure 3. Flow diagram of a proposed physiological pharmacokinetic model for

isometamidium

For each compartment, mass balance equations are written to describe the blood flow
rate, drug accumulation and drug elimination (Dedrick et aZ., 1972, 1973) by the
general equation:
Rate of = Rate of Rate of Rate of Rate of
accumulation entry - exit - metabolism - excretion
Specific adjustments for binding to macromolecules and specialized membrane
transport parameters are also incorporated in the model depending on the nature of
the drug and type of organ or tissue.
Physiological phamacokinetic analysis is not yet employed to any great extent in
veterinary pharmacokinetics. A few models, however, have been described for some
drugs in various animal species including actinomycin in dogs (Lutz et al., 1977),
adriamycin in rabbits (Harris and Gross, 1975), thiopental in dogs (Bischoff and
Dedrick, 1968) and salicylate in dogs (Chen et al., 1978). A physiological model to
study the disposition of compounds applied topically to swine has also been described
P iviere, 1988). Koritz (1983) has described an approach which combines
physiological (gastrointestinal flow) and compartmental models to describe drug
absorption in ruminants. Because the gastrointestinal tract is considered to be outside
the body, it is important that models which incorporate the gastrointestinal tract be
carefully designed with specific and valid assumptions to distinguish it from tissues or
organ compartments that can be represented by physiological parameters.
The proposed model for the antitrypanosomal drug isometamidium presented in
Figure 3 is based on experimental data of its serum and tissue concentrations (Kinabo
and Bogan, 1988a,b) and urinary and faecal excretion (unpublished data) in cattle.
The model assumes that: (1) the drug binds to tissue components with a high affinity,
(2) accumulation of the drug in liver occurs by active transport mechanism, (3) the
150

ratio between concentrations in the major tissue compartments such as the muscle
depot (injection site), liver and kidney, and those in serum is in the range of 100-1000
and (4) the primary route of its excretion is bile, and urinary excretion is insignificant.
This approach, unlike compartmental analysis, should be preferable for
characterization of isometamidium disposition because it incorporates a greater
number of realistic parameters. Isometamidium is a highly cationic drug which
exhibits complex kinetic characteristics. Compartmental analysis could not be used to
evaluate its pharmacokinetic behaviour because of its very low concentration in
serum, while urinary excretion data could not be used as an alternative approach due
to its negligible excretion in urine. It is rapidly cleared from serum and accumulates in
specific tissues and at the injection site over long periods. Serum concentrations did
not reflect its kinetics in tissues and at the injection site and the serum concentrations
alone could not provide adequate information to explain its long prophylactic property
of about l-5 months. Successful development of a physiological model for isometa-
midium would be valuable in predicting alterations in kinetics which might occur due
to haemodynamic changes in cases of trypanosomiasis, the major pathological feature
of which is anaemia.

POPULATION PHARMACOKINETIC MODELS

This is a recently introduced approach. Its conceptual basis of characterizing drug

disposition involves estimation of population mean kinetics, interindividual variability
and residual variability which includes methodological errors. Information on all these
aspects is important in determining dosage for individual patients, as evidence is now
available that average pharmacokinetic parameters alone are often not sufficient
(Steiner et al., 1984).
Data for population pharmacokinetic studies can be collected from patients
receiving the drug under investigation during their routine care (Beal, 1984; Sheiner,
1984). In this approach, only a few blood or plasma samples of each individual subject
are required but the number of subjects is usually large in order to estimate the
degree of individual variation and to identify the physiological parameters which can
reduce the variation (Sheiner, 1984; Riviere, 1988). Physiological parameters such as
weight, age and glomerular filtration rate are measured and these are correlated with
pharmacokinetic parameters. This permits data from animals in which very few
samples were collected to be used since the physiological data can be used to predict
the pharmacokinetic parameters (Riviere, 1988).
For data analysis, the method termed non-linear mixed effect model
(NONMEM) has been used and evaluated by several investigators (Fluhler et al.,
1984; Steimer et al., 1984). This method is appropriate for analysis of routine clinical
data (Steimer et al., 1984) and has the advantage of obtaining standard deviations of
random effects related to the variability between subjects (Fluhler et al., 1984).
Steimer et al. (1984) have described newer alternative methods for estimation of
population parameters which compare well with the NONMEM method.
Because this approach does not require many samples from individual subjects, it
is considered to be an attractive method for circumventing ethical problems of
frequent and long sampling times in both human and animal research. Few or no
studies using this approach have been reported in the veterinary literature.
 151

Nevertheless, it is viewed as a promising methodology for estimation of drug

disposition parameters on a herd basis and for tailoring dosage to individual patients
on the basis of physiological and pathological status (Riviere, 1988). Studies of
population characteristics of pharmacokinetic parameters between animal species
may also reveal some fundamental aspects of comparative pharmacology.

PHARMACOKINETIC-PHARMACODYNAMIC MODELS

In therapeutics, the ultimate aim of understanding the pattern of change in drug

concentrations in the body as a function of time is to make predictions about the
course and magnitude of drug effects. All the models outlined in the preceding
sections are designed to analyse drug concentration-time data alone, without
considering drug effects. In recent years, there has been a considerable interest in
developing models that can be used to analyse pharmacokinetic and pharmaco-
dynamic data simultaneously. This integrative approach is referred to as
pharmacokinetic-pharmacodynamic modelling. It has been used to characterize the
pharmacokinetic-pharmacodynamic relationships of several drugs in humans,
including d-tubocurarine (Sheiner et al., 1979), benzodiazepines (Colburn and Jack,
1987), nifodipine (Kleinbloesem et al., 1987) and other drugs which act on the central
nervous system (Paalzow, 1984). The development, application and future of
pharmacokinetic-pharmacodynamic models have been discussed by several authors
(Sheiner et al., 1979; Holford and Sheiner, 1981; Colburn, 1981,1987).
While pharmacokinetic models are valuable in predicting drug concentrations as a
function of dose and time, pharmacodynamic models relate drug concentration at the
locus of action with drug effect (Holford and Sheiner, 1981). Because both models
have a common factor, that is, concentration, they can be integrated to analyse
combined pharmacokinetic and pharmacodynamic data derived from non-steady state
experiments. The general picture of a pharmacokinetic and pharmacodynamic model
to represent the situation where the effect site does not correspond to a pharmaco-
kinetic compartment is presented in Figure 4. The mass of the drug which enters the
hypothetical effect compartment is considered negligible and therefore the
exponential for this compartment is ignored in the pharmacokinetic determination of
the mass of drug in the body (Sheiner et al., 1979). The general procedures of analysis
of pharmacokinetic and pharmacodynamic data have been described in detail
(Sheiner et al., 1979; Gibaldi and Perrier, 1982; Fuseau and Sheiner, 1984; Paalzow,
1984, Unadket et al., 1986). Pharmacokinetic parameter estimates are firstly
determined by fitting an appropriate pharmacokinetic model to the drug
concentration-time data. Then an appropriate pharmacodynamic model is fitted to
the effect versus time data. This gives the parameter estimates of the link model and
the pharmacodynamic model. Note that the overall pharmacokinetic-
pharmacodynamic model comprises a compartmental model, a hypothetical effect
compartment and a mathematical function for drug effect. The functions commonly
used to relate drug effects to concentrations are defined as follows:
152

Dose

Figure 4. Schematic representation of a pharmacokinetic-pharmacodynamic model.

A hypothetical effect compartment is directly linked to the central compartment of a
three-compartment mamillary model. k,, is the first-order rate constant for elimin-
ation from the central compartment; kIe is the first-order rate constant linking the
pharmacokinetic model to the effect compartment; and Ice, is the first-order rate
constant for drug removal from the effect compartment.

l. Enlax model: This is the simplest model which describes drug effect over a wide
range of concentrations, and is based on the hyperbolic relationship:

E max
E =
c+cE50
where E is the effect, C is the concentration, E is the maximum effect and CEso is
the concentration corresponding to 50% of the g&mum effect. When the drug effect
is measured as inhibition of activity such as decrease in blood pressure, the equation
becomes:

Emax ( - rnin)
E =
G50 - min) + Cc - miJ
where Cmin is the minimum effective concentration and CEO is the concentration
corresponding to 50% of the maximum inhibition of effect (Emax).

2. Sigmoid E,,,, model: This function is applicable when the concentration-effect

relationship is not hyperbolic, and is expressed as:

where N is an exponent (dimensionless slope parameter), and the other symbols are
as defined above.
 153

3. Linear model: In this model, the effect is assumed to be proportional to

concentration if the concentrations are low in relation to CEsO.Thus

E=SxC

where S is the slope of the line relating effect to concentration.

Drug effects and plasma concentrations are not always directly correlated.
Discrepancies from a direct relationship can be observed if there is a delay in
establishment of equilibrium between plasma concentration and effect site concent-
ration. Such equilibrium delays are recognized by hysteresis curves (anticlockwise
loops; Figure 5) which result when the pharmacological effects versus plasma
concentrations are plotted and the points connected in time order (Holford and
Sheiner, 1981; Fuseau and Sheiner, 1984). It is possible that delays of onset of effect
may also be due to multiple receptor activations (Paalzow, 1984) or formation of
active metabolites (Holford and Sheiner, 1981).

Plasma concentration

Figure 5. A hysteresis curve depicting equilibrium delay between plasma concent-

ration and the effect site.

The shortcomings and areas of improvement of pharmacokinetic-pharmaco-

dynamic models have been discussed in detail (Gibaldi and Perrier, 1982; Colburn,
1987; Sheiner, 1984). Some of the major limitations include reliance on compart-
mental models and the property of linking effect site exclusively to the sampled
compartment. Use of physiological models and inclusion of drug receptor interaction
into the effector site model have been suggested as possible ways of improving this
approach.
Pharmacokinetic-pharmacodynamic analysis has several advantages. Primarily, it
is possible to delineate the factors which influence pharmacological effects in a
quantitative manner. In addition, it allows extremes of drug response to be modelled.
To date, no reports have appeared in the veterinary literature with regard to the
154

application of pharmacokinetic-pharmacodynamic models in studying drugs designed

for use in domestic animals. Evidence is now growing that this approach has great
potential in yielding relevant data for determination of rational dosing regimens for
therapeutic purposes. In fact, approaches of this type have been advocated in
veterinary pharmacology (Short and Lees, 1984).

CONCLUSION

It is hoped that this review has summarized the different approaches which are
currently used to analyse kinetic data and will stimulate interest in the application of
some of these novel approaches to studying drug disposition in various species of
domestic animal. Undoubtedly, without the use of alternative and/or new models, it
would be difficult to improve our experimental approaches, and to understand
complex pharmacological differences between animal species.

ACKNOWLEDGEMENT

This paper is dedicated to the late Professor James A. Bogan who inspired us to
review the subject.

REFERENCES

Aliu, Y.O. and Odegaard, S., 198.5. Pharmacokinetics of diminazene in sheep. Jourt~~Z ofPharmacokinetics
and Biopharmaceudcs, 13,173-1&l
Baggot, J.D., 1977. Principles of drug disposition in domestic animals. The Basis of Veterinary Clinical
PhurmacoIogy, (W.B. Saunders, Philadelphia)
Baggot, J.D., 1983. Clinical utility and limitations of pharmacokinetics. In: Y. Ruckebusch, P.L. Toutain
and G.D. Koritz, (eds.), Veterinary Pharmacology and Toxicology Proceedings from the 2nd European
Association for Veferhaty Pharmacology and Toxicology, Toulouse, France, 1982, (MTP Press,
Lancaster)
Beal, S.L., 1984. Population pharmacokinetic data and parameter estimation based on their first two
statistical moments. Drug Merubolism Reviews, 15, 173-193
Beal, S.L., 1987. Some clarifications regarding moments of residence times with pharmacokinetic models.
Journal of Phamtacokinetics and Biopharmaceutics, l&75-92
Benet, L.Z., 1985. Mean residence time in the body versus mean residence time in the central
compartment. Journal of Pharmacokinetics and Biophumzaceutics, 13,555-558
Benet, L.Z. and Galeazzi, RL., 1979. Noncompartmental determination of the steady-state volume of
distribution. Journal of Pharmaceutical Sciences, 68,1071-1074
Bialer, M., 1980. A simple method for determining whether absorption and elimination rate constants are
equal in the one-compartment open model with first-order processes. Journal of Pburmacokinetics
and Biophumzaceutics, 8,111-113
Bischoff, K.B. and Dedrick, RL., 1968. Thiopental pharmacokinetics. Journal of Phurmoceuticnl Sciences,
57,1346-13X
Bretzlaff, K.N., Neff-Davis, CA., Ott, RS., Koritz, G.D., Gustafsson, B.K. and Davis, L.E., 1987.
Florfenicol in non-lactating dairy cows: pharmacokinetics, binding to plasma proteins, and effects on
phagocytosis by blood neutrophils. Journal of Veeterinary Pharmacology and Therapeutics, 10,233-240
Chay, S., Wood, W.E., Nugent, T. and Blake, J., 1982. The Ipharmacology of nonsteroidal anti-
inflammatory drugs in the horse: punixin meglumine (Benamine ). Equine Practice, 4,16-23
Chen, C.N., Coleman, D.L., Andrade, J.D. and Temple, A.R, 1978. Pharmacokinetic model for salicylate
in cerebrospinal fluid, blood, organs and tissues. Journal of Pharmaceutical Sciences, 67,38-45
Chennavasin, P., Johnson, R.A. and Brater, D.C., 1981. Variability in derived parameters of furosemide
pharmacokinetics. Journal of Phurmacokinetics and Biopharmaceutics, 9,623-633
 15s

Cobelli, C. and Toffolo, G., 1984. Compartmental vs. noneompartmental modeling for two accessible
pools. American Journal of Physiology, 247, (Regulatory Integrative and Comparative Physiology, 16)
R488-R496
Colbum, WA., 1981. Simultaneous pharmacokinetic and pharmacodynamic modeling. Journal of
Phamacokinetics and Biophamzaceutics, 9,367-388
Colburn, W.A., 1987. Pharmacokinetic/pharmacodynamic modeling: What it is! Journal of
Pharmacokinefics and Biopharmaceutics, lS,S4S-553
Colbum, WA. and Jack, M.L., 1987. Relationships among CSF drug concentrations, receptor binding
characteristics, and pharmacokinetic and pharmacodynamic properties of selected 1,4-substituted
benzodiazepines. Clinical Pha~acokinetics, 13,179-190
Cutler, D.J., 1978. Theory of the mean absorption time; an adjunct to conventional bioavailability studies.
Journal of Pharmacy and Pharmacology, 30,476-478
DArgenio, D.Z., 1981. Optimal sampling times for pharmacokinetic experiments. Journal of
Phurmacokinetics and Biophamtaceutics, 9,739-756
Davis, L.E., Neff-Davis, CA., Koritz, G.D., Bevill, RF., Sharma, G.C., Langton, V.C. and Munsiff, LJ.,
1987. Effect of organic vehicles on the pharmacokinetics of aminophylline administered intravenously
to goats. Journal of Veterinary Pharmacology and Therapeutics, 10, 144-149
Dedrick, RL., Forrester, D.D., Cannon, J.N., El Dareer, SM. and Mellett, L.B., 1973. Pharmacokinetics
of 1-fl-o-arabinosylcytosine (ara-c) deamination in several species. Biochemical Pharmacology, 22,
24QS-2417
Dedrick, RL., Forrester, D.D. and Ho, D.H.W., 1972. In vitro and in viva correlation of drug metabolism
- deamination of l-p-o-arabinofuranosylcytosine. BiochemicalPharmacology, 21,1-16
Delbeke, F.T., Debackere, M., Desmet, N. and Stevens, M., 1986. Pharmacokinetics and diuretic effect of
bumetanide following intravenous and intramuscular administration to horses. Journal of Vebzrinary
Pharmacology and Therapeutics, 9,310-317
DiStefano, J.J. III., 1982. Noncompartmental vs. compartmental analysis: some bases for choice. American
Journal of Physiology, 243, (Regulatory, Integrative and Comparative Physiology, 12) Rl-R6
DiStefano, J.J. III. and Landaw, E., 1984. Multiexponential, multicompartmental, and noncompartmental
modeling. I. Methodological limitations and physiological interpretations. American Journal of
Physiology, 246, (Regulatory, Integrative and Comparative Physiology, 15) R6Sl-R664
Dunne, A., 1986. An iterative curve stripping technique for pharmacokinetic parameter estimation.
Journal of Pharmacy and Phamtacotogy, 38,97-101
Fluhler, H., Huber, H., Widmer, E. and Brechbuhler, S., 1984. Experiences in the application of
NONMEM to pharmacokinetic data analysis. Drug Metabolism Reviews, 15,317-339
Fuseau, E. and Sheiner, L.B., 1984. Simultaneous modeling of pharmacokinetics and pharmacodynamics
with a nonparametric pharmacodynamic model. Clinical Pharmacology and Therapeutics, 35,733-741
Gerlowski, L.E. and Jain, RK, 1983. Physiologically based pharmacokinetic modeling; principles and
applications. Journal of Pham2aceuticat Sciences, 72,1103-1127
Gibaldi, M. and Perrier, D., 1982. Pharmacokinetics, 2nd edn. (Marcel Dekker, New York)
Hanna, RM., Borchard, RE. and Schmidt, S.L., 1988. Effect of diuretics on ketamine and sulfanilate
elimination in cats. Journal of Veterinary Pharmacology and Therapeutics, 11, 121-129
Harris, Ph. and Gross, J.F., 1975. Preliminary pharmacokinetic model for adriamycin. Cancer
Chemotherapy Repons, 54,819-825
Himmelstein, K.J. and Lutz, RJ., 1979. A review of the applications of physiologically based
pharmacokinetic modeling. Journal of Pharmacokinetics and Biophamzaceutics, 7,127-145
Holford, N.H.G. and Sheiner, L.B., 1981. Undefitanding the dose-effect relationship: clinical application
of pharmacokinetic-pharmaccdynamic models. Clinical Pharmacokinetics, 6,429-453
Jemigan, A.D., Wilson, RC., Booth, N.H., Hatch, RC. and Akbari, A., 1988a. Comparative pharmaco-
kinetics of yohimbine in steers, horses and dogs. Canadian Journal of Ve&rinaty Research, 52,172-176
Jemigan, A.D., Wilson, R.C., Hatch, RC. and Kemp, D.T., 1988b. Pharmacokinetics of gentamicin after
intravenous, intramuscular, and subcutaneous administration in cats. American Journal of Veterinary
Research, 49,32-35
Kinabo, L.D.B. and Bogan, JA., 1988a. Solid-phase extraction and ion-pair reversed-phase HPLC of
isometamidium in bovine serum and tissues. Acta Tropica, 45,X.5-170
Kinabo, L.D.B. and Bogan, J.A., 1988b. Pharmacokinetic and histopathological investigations of
isometamidium in cattle. Research in Veterinary Science, 44,267-269
Kinabo, L.D.B. and Nielsen, P., 1986. Sulfatroxazole: pharmacokinetics, metabolism and urinary excretion
in goats and pigs. Journal of Veterinary Pharmacology and Therapeutics, 9,SS-62
Kleinbloesem, C.H., van Brumelen, P. and Breimer, D.D., 1987. Nifedipine: relationship between
pharmacokinetics and pharmacodynamics. Clinical Pharmacokinetics, l2,12-29
Knoppezt, N.W., Nijmeijer, SM., van Duin, C.T.M., Korstanje, C., van Gogh, H. and van Miert,
A.S.J.PA.M., 1988. Some pharmacokinetic data of aditoprim and trimethoprim in healthy and
tick-borne fever infected dwarf goats. Journal of Veterinary Pharmacology and Therapeutics, 11,
135-144
156

Koritz, G.D., 1983. Influence of ruminant gastrointestinal physiology on the pharmacokinetics of drugs in
dosage forms administered orally. In: Y. Ruckebusch, P.L. Toutain and G.D. Koritz, (eds.), Veterinary
Pharmacology and Toxicologv. Proceedings porn the 2nd European Association for Veterinary
Pharmacology and Toxicology, Toulouse, France, I982, (MTP Press, Lancaster) pp. 151-163
Koritz, G.D., McKieman, B.C., Neff-Davis, CA. and Munsiff, I.J., 1986. Bioavailability of four slow-
release theophylline formulations in the Beagle dog. Journal of Veferinary Pharmacology and
Therapeutics, 9,293-302
Landaw, E. and DiStefano, J.J. III., 1984. Multiexponential, multicompartmental, and noncompartmental
modeling. III. Data analysis and statistical considerations. American Journal of Physiology, 246,
(Regulatory, Integrative and Comparative Physiology, U), R665-R677
Lees, P., Ayliffe, T., Maitho, T.E. and Taylor, J.B.O., 1988. Pharmacokinetics, metabolism and excretion
of phenylbutazone in cattle following intravenous, intramuscular and oral administration. Research in
Veterinary Science, 44,57-67
Lutz, RJ., Galbraith, W.M., Dedrick, RL., Shrager, R and Mellet, L.B., 1977. A model for the kinetics of
distribution of actinomycin in the beagle dog. Journal of Pharmacology and Experimental
Therapeutics, 200,469-478
Mintun, M., Himmelstein, K.J., Schroder, R.L., Gibaldi, M. and Shen, D.D., 1980. Tissue distribution
kinetics of tetraethylammonium ion in the rat. Journal of Pharmacokinedcs and Eiopharmaceufics, 8,
373-409
Notari, RE., 1975. Biopharmaceutics and Pharmacokinetics: an Infroducrion, 2nd edn. (Marcel Dekker,
New York)
Nuesch, EA., 1984. Noncompartmental approach in pharmacokinetics using moments. Lkug Metabolism
Reviews, 15,103-131
Odegaard, SA. and Rastaad, A., 1987. Pharmacokinetics of sulphaphenazoie in cattle. Journal of
Veterinary Pharmacology and Therapeutics, 10,83-84
Paalzow, L.K., 1984. Integrated pharmacokinetic-dynamic modeling of drugs acting on the CNS. Dnrg
Metabolism Reviews, 15,383-400
Pedersen, P.V., 1977. Curve fitting and modeling in pharmacokinetics and some practical experiences with
NONLIN and a new program FIJiWIT. Journal of Pharmacokinefics and Biopharmaceutics, 5,
513-531
Rescigno, A. and Beck, J.S., 1987. The use and abuse of models. Journal of Phatmacokinerics and
Biophamzaceutics, 15, 327-340
Riegelman, S. and Collier, P., 1980. The application of statistical moment theory to the evaluation of in
viva dissolution time and absorption time. Journal of Pharmacokinetics and Biopharmaceutics, 8,
509-534
Riond, J.-L. and Riviere, J.E., 1988. Multiple intravenous dose pharmacokinetics and residue depletion
profile of gentamicin in pigs. Journal of Veterinary Pharmacology and Therapeutics, 11,210-214
Riviere, J.E., 1988. Veterinary clinical pharmacokinetics. Part II. modeling. Compendium on continuing
education for thepractising veterinarian, 10,314-328
Rowland, M., 1984. Physiologic pharmacokinetic models: Relevance, experience, and future trends. Dnrg
Metabolism Reviews, 15, X-74
Rowland, M. and Tucker, G., 1980. Symbols in pharmacokinetics. Journal of Pharmacokinefics and
Biopkmaceutics, 8,497-507 -
Sanders, P., Guillot, P. and Mourot, D., 1988. Pharmacokinetics of a long-acting chloramphenicol
formulation administered by intramuscular and subcutaneous routes in cattle. Journal of Veterinary
Pharmacolofl and Therapeutics, 11,183-Ml
Sedman, A.J. aid Wagner, J.G., 1976. CSTRIP, a Fortran IV computer program for obtaining initial
nolvexnonential uarameter estimates. Journal ofPharmaceutical Sciences, 65, 1006-1010
Segrk, G., i984. Relevance, experiences and trendssin the use of compartmental models. Lkug Merabokm
Reviews, l&7-53
Semrad, SD., Hardee, G.E., Hardee, M.M. and Moore, J.N., 1985. Fiunixin meglumine given in small
doses: pharmacokinetics and prostaglandin inhibition in healthy horses. American Journal of
Veterinary Research, 46,2474-2479
Sheiner, L.B., 1984. The population approach to pharmacokinetic data analysis: rationale and standard
data analysis methods. Drug Metabolism Reviews, 15,153-171
Sheiner, L.B., 1987. Commentary to pharmacokinetic/pharmacodynamic modeling: What it is! Journal of
Pharmacokinetics and Biopharmaceutics, 15,553-555
Sheiner, L.B., Stanski, D.R, Vozeh, S., Miller, RD. and Ham, J., 1979. Simultaneous modeling of
pharmacokinetics and pharmacodynamics: application to d-tubocurarine. Clinical Pharmacology and
Therapeutics, 25,358-371
Short, CR and Lees, P., 1984. Editorial. Journal of Veterinary Pharmacology and Therapeutics, 7,253-254
Soback, S., 1988. Pharmacokinetics of single doses of cefoxitin given by the intravenous and intramuscular
routes to unweaned calves. Journal of Veterinary Pharmacology and Therapeutics, ll, lSS-162
 157

Soback, S. and Ziv, G., 1988. Pharmacokinetics and bioavailability of ceftriaxone administered intra-
venously and intramuscularly to calves. American Journal of Veterikay Research, 49,535-X%
Steimer, J.L., Mallet, A., Golmard, J.L. and Boisvieux, J.F., 1984. Alternative approaches to estimation of
population pharmacokinetic parameters: Comparison with the nonlinear mixed-effect model. Drug
Metabolism Reviews, 57,205240
Teorell, T., 1937. Kinetics of distribution of substances administered to the body. I. The extravascular
modes of administration. Archives Intemationale de Phurmacodynamie, 57,20522.5
Unadkat, J.D., Bartha, F. and Sheiner, L.B., 1986. Simultaneous modeling of pharmacokinetics and
pharmacodynamics with nonparametric kinetic and dynamic models. Clinical Phumtacology and
lkrapeutics, 40,86-93
Vaughan, D.P. and Hope, I., 1979. Applications of a recirculatory stochastic pharmacokinetic model:
Limitations of compartmental models. Journal of Pharmacokinetics and Biophannaceutics, 7,207-225
Wagner, J.G., 1976. Linear pharmacokinetic models and vanishing exponential terms: implications in
pharmacokinetics. Journal of Phurrnacokinetics and Biopharmaceutics, 4,39542.5
Wertz, E.M., Benson, G.J., Thurman, J.C., Tranquilli, W.J., Davis, L.E. and Koritz, G.D., 1988.
Pharmacokinetics of thiamylal in cats. American Journal of Veterinary Research, 49,1079-1083
Wijnand, H.P., 1988. Pharmacokinetic model equations for the one- and two-compartment models with
first-order processes in which the absorption and exponential elimination or distribution rate
constants are equal. Journal of Pharmacokinetics and Biopharmaceutics, 16,109-X28
Yamaoka, K., Nakagawa, T. and Uno, T., 1978. Statistical moments in pharmacokinetics. Journal of
Phumacokinetics and Biopharmaceutics, 6,547-S%
Ziv, G., Nouws, J.F.M. and Van-Ginneken, CAM., 1982. The pharmacokinetics and tissue levels of
polymyxin B, colistin and gentamicin in calves. Journal of Veterinary Pharmacology and Therapeutics,
5,45-c%
Ziv, G., Soback, S., Bor, A. and Kurtz, B., 1986. Clinical pharmacokinetics of flumequine in calves. Journal
of Veterinary Pharmacology and Therapeutics, 9, 171-182

(Accepted: 24 December 1988)