antipyrine dogs horse

Pharmacokinetic-pharmacodynamic relationship
Jd Baggot
To cite this version:
Jd Baggot. Pharmacokinetic-pharmacodynamic relationship. Annales de Recherches Vétérinaires,
INRA Editions, 1990, 21 (suppl1), pp.29s-40s. <hal-00901990>
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Pharmacokinetic-pharmacodynamic relationship
JD Baggot
Irish
Equine Centre, Johnstown, County Kildare, Ireland
(Pharmacokinetics of Veterinary Drugs.
11-12 October 1989,
Foug6res, France)
The dose-effect relationship can be determined by linking pharmacokinetic drug behavior with information on pharmacodynamic activity. This requires that the quantifiable concentrations of drug (or metabolites) in the plasma (systemic circulation) are related to the concentration at
the site of action. Using the pharmacokinetic parameters and a pharmacokinetic-pharmacodynamic
model, it is possible to predict the pharmacodynamic response to certain drugs; this provides useful
information for understanding drug action and to determine dosage regimen.
Summary―
pharmacokinetic-pharmacodynamic model
Résumé― Relations
vent être déterminées
pharmacocinétiques-pharmacodynamiques. Les relations dose!ffetpeu-
en reliant le comportement pharmacocinétique d’un principe actif à l’activité
Celà requiert que les concentrations mesurables dans le plasma soient corrélées avec les concentrations au site d’action. En utilisant les paramètres pharmacocinétiques et un
modèle pharmacocinétique!harmacodynamique, il est possible, pour certains médicaments, de
prédire la réponse pharmacodynamique. Cela donne des informations utiles pour comprendre l’action d’un principe actif et pour déterminer les posologies.
pharmacodynamique.
modèle pharmacocinétique-pharmacodynamique
INTRODUCTION
relationship between the dose of a
drug and the clinically observed pharmacological effect may be quite complex. An
understanding of the dose-effect relationship can generally be obtained by linking
pharmacokinetic behavior with information
on pharmacodynamic activity. Pharmacok-
The
inetics defines the mathematical relationthat exists between the dose of a
ship
drug and the plasma concentration-time
profile of the drug. Pharmacodynamics extends this relationship to the correlation
between plasma drug concentrations and
the pharmacological effect. The intensity
of the pharmacological effect generally determines whether the desired clinical effect or a toxic effect is produced. An inherent assumption is that the quantifiable
concentrations of drug in the plasma (systemic circulation) are related to the concentrations at the site of action.
The clinical utility of pharmacokinetics
relies on the premise that a therapeutic
range of plasma concentrations can be defined for each drug. The width of this
range reflects the relative safety of the
drug and, together with half-life, influences
the dosing interval. Metabolites may have
to be considered when they possess pharmacological activity that contributes to the
therapeutic or toxic effect. For drugs with a
narrow margin of safety or antimicrobial
agents that can rapidly induce bacterial resistance, the clinician must weigh the adverse potential of the dosage regimen and
duration of treatment against effectiveness
in treating the disease condition. Since antimicrobial agents do not produce pharmacological effects at usual dosage, any
range of plasma concentrations defined relates to quantitative susceptibility (MIC value, determined in vitro) of pathogenic microorganisms and the induction of an
undesirable pharmacological (toxic) effect.
The latter may often be related to the duration of antimicrobial therapy rather than
the peak plasma concentration attained at
usual dosage. Since dosage regimens are
generally based on pharmacokinetic parameters, it is relevant to distinguish between pharmacological and antimicrobial
agents with regard
to the definition of ther-
apeutic plasma concentrations.
THERAPEUTIC CONCENTRATIONS
For many
the
of
concentratherapeutic range
plasma
tions has been defined (table I). It is assumed that the plasma drug concentration
range defined in humans is applicable to
domestic animals. On this basis, the dosing rate of a drug that will produce similar
pharmacological effects in different species can be calculated. This concept has
been established for a variety of drugs. For
example, to produce a sustained bronchodilator effect with theophylline (phos-
pharmacological agents,
phodiesterase inhibitor), an average
steady-state plasma concentration of 10
,ug/ml is required. Based on the therapeutic
range of plasma concentrations and taking
into account the systemic availability (F)
and clearance (CI) of theophylline, oral
dosage regimens for aminophylline can be
calculated. The dosing rates that will produce equivalent bronchodilator effects in
horses or cats (5 mg/kg at 12 h intervals)
and in dogs (10 mg/kg at 8 h intervals) are
distinctly different.
For drugs that produce pharmacological
effects at very low plasma concentrations
(such as reserpine) the limit of assay sensitivity may not allow therapeutic plasma
concentrations to be defined or the relationship between plasma concentrations
and pharmacological effect to be established.
The clinical effectiveness of a drug
product can be influenced by the dosing
rate, which can be defined as the systemically available dose/unit time:
Fx dose
dosingrate
dosing =
interval
where F is the fraction of the dose which
enters the systemic circulation unchanged.
In addition, formulation of the dosage form
and route of administration may affect the
efficacy and safety of the drug. These factors collectively contribute to the plasma
concentration-time profile.
APPROACH TO PHARMACODYNAMICS
sensitivity to observed differences in
pharmacological response.
In selecting a model to analyze the relationship between plasma concentration
and pharmacological effect of a drug, the
tor
foremost consideration is the character of
the particular response (Schwinghammer
and Kroboth, 1988). Before an appropriate
pharmacodynamic model can be selected,
effect versus time plots of the data from
each individual animal in the experimental
group should be examined visually to obtain information about the dose-response
relationship, the time course of effect after
different doses and the behavior of the
physiological system of interest in the absence of drug, such as after placebo administration. An examination of individual
animal plots of pharmacological effect versus plasma drug concentration will assist
in the selection of a model. Such plots may
reveal important characteristics of the effect-concentration relationship, such as
linearity, the maximum achievable effect,
development of tolerance, a lag between
peak concentration and peak effect, and
the degree of individual variation in response.
Pharmacodynamics is the study of the relationship between the concentration of a
drug at the site of action (biophase concentration) and the resultant pharmacological effects. Since it is seldom possible to
measure the biophase drug concentration,
pharmacodynamic analyses frequently require making the assumption that the concentration in the plasma is related to the
concentration at the receptor site. Thus, by
combining the plasma concentration-time
profile with some quantifiable measure of
drug response in pharmacodynamic models, an understanding of the concentration-effect relationship can be obtained.
Studies of plasma concentration-effect relationships may provide information on the
contribution of
species variations
in recep-
Although the plasma concentrationeffect relationship has been described for
certain drug classes (anti-arrhythmics, histamine H
-receptor antagonists, cardiac
2
glycosides, neuromuscular blocking drugs),
pharmacodynamic modelling is empirical.
To gain a more complete understanding of
the dose-plasma concentration-effect relationship, the use of combined pharmacokinetic-pharmacodynamic models that
incorporate an effect compartment may be
necessary.
SPECIES DIFFERENCES IN DOSAGE
Appropriate dosage
takes into account
for different species
species variations in
both the
pharmacokinetic behavior and
pharmacodynamic activity of the drug. The
requirement for species differences in
dose level may be attributed to variations
in systemic availability (extent of absorption), particularly from the gastrointestinal
tract, or the distribution of the drug, or may
be due to differences in the sensitivity of
drug receptor sites. The low dose levels,
relative to those for dogs, of morphine for
cats and xylazine for cattle may be due to
higher sensitivity of receptor sites for these
drugs in the central nervous system (pharmacodynamic variation). The wide species
variations in dose level and sensitivity to
the neuromuscular blocking effect of succinylcholine has been attributed to differences in activity of plasma pseudocholinesterase. This source of variation could be
considered to have a pharmacokinetic
rather than pharmacodynamic basis, since
it is metabolism of the drug that accounts
for the species differences. The majority of
species differences in pharmacological effects that result from fixed dosage of a
drug is due to variations in pharmacokinetic processes, principally the rate of hepatic
microsomal metabolism (oxidative reactions and glucuronide synthesis). These
differences can be accommodated by adjusting the dosing interval, for example,
the dosing interval for aspirin in cats is 48
h compared with 12 h in dogs, since the
cat has a relative deficiency in glucuronyl
transferase activity.
In the various
mals, drugs
are
species of laboratory ani-
generally
eliminated
more
rapidly than in domestic animals due to the
higher rate of basic metabolism in the former. Since basic metabolism of warmblooded animals is a function of body surface area rather than body weight, small
animal species require higher doses of
drugs and shorter dosing intervals than
larger species. Extrapolation of pharmacological and toxicological data based on
metabolic weight (Wbldyo .756) appears to
apply within the group of ruminant animals
and monogastric herbivores as well as
from one carnivorous species to another
(van Miert, 1989). When wide variations in
response
are
observed in
some
animal
species, with no relationship to animal
size, interspecies predictions on the doseresponse relationship are unlikely to be
valid.
The metabolism rate of
some
drugs is
dose-dependent in certain species
at dose
levels above a certain limit. The dose level
at which a major elimination pathway for a
drug becomes capacity limited determines
the clinical significance of dose-dependent
elimination. Unless dose-dependent elimination is a feature of therapeutic dosage,
as is the case with phenylbutazone and
phenytoin, this limitation in capacity to
eliminate a drug is relatively unimportant.
PHARMACOKINETIC PARAMETERS
Pharmacokinetic parameters describe drug
absorption and disposition processes in
quantitative terms and provide a basis for
calculation of dosage regimens.
The basic pharmacokinetic parameters
are clearance (CI), which measures the
ability of the body to eliminate the drug,
and volume of distribution (V
), which
d
quantifies the apparent space available, in
both the systemic circulation and the tissues of distribution, to contain the drug.
Another important parameter is systemic
availability (F) (extent of absorption), which
expresses the fraction of the dose that ensystemic circulation unchanged
following parenteral (non-vascular) or oral
ters the
administration.
Clearance
Species variations in clearance and changes induced by the presence of disease
The systemic clearance of a drug reflects
the sum of the clearances from all individual organs that play a role in eliminating the
drug. It can be calculated by dividing the
systemically available dose by the area under the plasma concentration-time curve
conditions or in certain physiological states
can be attributed to differences in activity
of the elimination processes for the drug.
Allowance for species variations or changes in clearance can be made by appropriate adjustment of the dosing rate. The prevailing assumption is that plasma
concentrations within the usual therapeutic
range will produce an equivalent pharmacological response in terms of drug efficacy
and safety (that is, pharmacodynamic activity is assumed to remain unchanged).
(AUC):
The AUC can be calculated either as the
integral of the equation describing the plasma concentration-time curve or by the
trapezoidal rule, using the measured plasma concentrations at the blood sampling
times (Baggot, 1977). It is only when the
drug is administered intravenously that the
dose can be assumed to be completely
available systemically.
The calculation of clearance, based on
area under the curve measurements, of
drugs that follow first-order kinetics is independent of the number of compartments in
pharmacokinetic model. The clearance
of most drugs is constant at the concentrations encountered clinically, since their
elimination obeys first-order kinetics. For
drugs that exhibit saturable or dosedependent elimination, clearance will vary
depending upon the plasma concentration
achieved. It should be noted that when
blood (rather than plasma) concentration is
used to define clearance, the maximum
clearance possible is equal to the sum of
blood flows to the various organs of elimination (liver, kidney, lung and other tissues
in which elimination processes occur).
Clearance is probably the most important pharmacokinetic parameter to consider in designing drug dosage regimens.
In drug therapy, the objective of the dosage regimen is to maintain plasma concentrations within the therapeutic concentration range. The steady-state plasma
concentration (Cp!ss!) attained by continuous infusion or the average plasma level
following multiple dosing (repeated administration of a fixed dose at a constant dosing interval) depends upon systemic clearance:
a
required to reach steady state or
change from one steady-state concentration to another depends solely upon the
half-life of the drug. Knowledge of the plasThe time
to
concentrations that are associated with
effects and of certain pharmacokinetic parameters is required in designing the dosing rate. Otherwise, dosage has
to be based on experience with use of the
drug and clinical assessment of the pharmacological effects produced.
Although clearance describes drug elimination from the body, it is expressed in
units of flow rather than time (as in halflife). This implies that clearance is a poor
indicator of drug persistence in the body.
ma
therapeutic
Volume of distribution
The volume of distribution, which relates
the amount of drug in the body to the concentration in the plasma, provides an estimate of the extent of distibution (rather
than describing the distribution pattern) of
the drug. This parameter (volume term)
can be calculated from the equation:
the fluctuation in steady-state concentrations on multiple dosing, but it does not influence the average steady-state concentration. Volume of distribution is sensitive
to plasma protein binding and can therefore be expected to vary in disease conditions where the protein binding is altered.
Volume of distribution is used in calcu-
lating the dose (mg/kg) required to produce a plasma drug concentration within
the therapeutic range: dosei
v Cp(t
) x
her
=
(area)d
V
where
/3 is the overall elimination rate constant of the drug, determined from the
elimination phase of the disposition curve.
Volume of distribution is determined by
certain physicochemical properties (pK
a
and lipid solubility) of the drug and the degree of binding to plasma proteins and extravascular tissues. This volume term can
vary among species due to differences in
body composition, particularly anatomical
features of the gastrointestinal tract. Drugs
that are relatively polar (penicillins, cephalosporins, aminoglycosides, non-steroidal
anti-inflammatory drugs) may have volumes of distribution similar to the extracellular fluid volume (200-300 ml/kg). It must
be emphasized, however, that the volume
of distribution does not relate to a physiological space and its magnitude cannot be
used to predict the distribution pattern of a
drug. Some lipid-soluble organic bases
(clonidine, propranolol and morphine)
are effective at low plasma concentrations (<100 ng/ml) and have large volumes
of distribution (>1 I/kg). In ruminant species, lipophilic bases passively diffuse
from the systemic circulation into ruminal
fluid (pH 5.5-6.5), where they become
trapped by ionization. This is a feature of
their usual pattern of distribution. The
magnitude of the volume of distribution of
a drug affects the half-life of the drug and
Administration of the drug by other than
the intravenous route may require upward
adjustment of the dose level to compensate for incomplete systemic availability.
Half life
The half-life of a drug expresses the time
required for the plasma concentration, as
well as the amount in the body, to decrease by 50% through the process of
elimination. For most drugs, the half-life is
independent of the dose administered,
since at therapeutic dosage overall elimination obeys first-order kinetics. The halflife of a small number of drugs is dosedependent, that is, elimination is zeroorder, in certain species. This can generally be attributed to saturation of a major
pathway of metabolism.
The half-lives of drugs that undergo extensive hepatic metabolism vary widely
among domestic animal species. The herbivorous species (horses and ruminant animals) generally metabolize lipid-soluble
drugs more rapidly than the carnivorous
species (dogs and cats). However, there
are notable exceptions to this trend, such
as theophylline in horses (Errecalde et al,
1984; Ingvast-Larsson et al, 1985) and
phenylbutazone (weak organic acid) in cattle (De Backer et al, 1980; Eberhardson et
weight.
With the notable
exception of the
human, antipyrine intrinsic clearance
was
directly proportional to liver weight
(Boxenbaum, 1980). Plasma antipyrine
also
half-life is
a
useful index of the rate of he-
patic metabolism (microsomal oxidation) of
a variety of drugs, but it does not reflect
the activity of all hepatic microsomal metabolic pathways (Vesell et al, 1973).
Species variations in the half-life of
drugs that are eliminated by renal excretion (penicillins, cephalosporins and aminoglycoside antibiotics) are not of clinical sig-
al, 1979; Martin et al, 1984). These excepdefy explanation at the present time.
tions
Most drugs that are eliminated mainly
by hepatic metabolism have shorter halflives in horses than in dogs, while the halflife in humans may be considerably longer
(table II).
It has been shown in a variety of mammalian species that hepatic blood flow is
approximately equal to 1.5 I/min/kg liver
nificance. Their half-lives are generally
longer and clearances lower in horses than
in dogs, while volumes of distribution are
similar in both species (table 111). This observation can be related to the species difference in efficiency of renal excretion
mechanisms (Baggot, 1977).
For drugs that are eliminated by renal
excretion (unchanged in the urine), allometric scaling of data obtained in animals
can be used to predict values of the pharmacokinetic parameters for these drugs in
humans (Mordenti, 1985).
The physiological basis of species variations in the half-life of drugs that are eliminated by a combination of biotransformation and excretion processes could be
ascribed to differences in the rates of
metabolic pathways and the influence of
urinary pH on the extent of renal tubular
reabsorption of unchanged (parent) drug.
The excretion of acidic drugs with pK
a values within the range of urinary pH (5-8),
such as phenobarbital and sulphonamides, is enhanced in alkaline urine (horses) and decreased in acidic urine (dogs).
The converse applies to organic bases (trimethoprim and metronidazole). Urinary pH
will affect the excretion rate of a drug only
when tubular reabsorption occurs and a
fraction of the dose is excreted unchanged
in the urine.
Half-life, in conjunction with the range of
therapeutic plasma concentrations, is used
to select the dosing interval for drugs that
show a relationship between half-life and
the duration of the pharmacological effect.
The half-life provides a good indication of
the time required to reach a desired
steady-state concentration when the drug
is administered by continuous intravenous
infusion. After infusing for a period corresponding to 4 times the half-life of the
drug, the plasma concentration will be
within 90% of the eventual steady-state
concentration.
When selective avid binding of a drug to
tissues occurs, which is unrelated to the
principal pharmacological effect of the
drug, half-life may not reflect the gradual
removal of the bound drug. This is particularly so when the amount bound represents only a small fraction of the dose administered. Although this situation may not
be of clinical significance, it represents a
serious shortcoming in the use of half-life
to predict withdrawal time for a drug in
food-producing species.
Systemic availability
The formulation of a drug product and
route of administration determine the systemic availability of the drug, while the rate
of absorption may influence the duration of
the pharmacological effect.
The usual technique for estimating systemic availability of a drug uses the method of corresponding areas. This entails
comparison of the total area under the
plasma concentration-time curve after
non-vascular (po, im, sc) administration
with that after intravenous injection of the
drug (using appropriate dosage forms) in
the same animals: F (!UCA4L/C!). This
technique for estimating systemic availability (sometimes called bioavailability) is
based on the assumption that clearance of
the drug is not changed by the route of administration.
=
The systemic availability of a drug administered orally may be less than 100%,
either because the drug is incompletely absorbed or is metabolized in the gastrointestinal tract (lumen or mucosa) or by the liver
before reaching the systemic circulation
(’first-pass’ effect). For drugs with high hepatic clearances (such as propranolol, lidocaine and morphine), it can be predicted
that the ’first-pass’ effect would substantially decrease their systemic availability after
oral administration. Because of species differences in digestive physiology and in the
capacity of the liver to metabolize lipidsoluble drugs, wide species variations in
the extent of the ’first pass’ effect on drug
products administered orally can be ex-
pected to occur.
Incomplete systemic availability of drugs
from parenteral dosage forms administered intramuscularly can be attributed either to precipitation of drug at the injection
site or tissue irritation induced by constituents of the formulation. The formulation of
each parenteral preparation must be considered in specifying the withdrawal time
for a drug. Location of the injection site can
cause variations in systemic availability
and rate of absorption of drugs administered as aqueous suspensions or other
sustained release preparations. By affecting the plasma concentrations attained,
these variations in absorption can significantly influence the pharmacological effects produced or the effectiveness of antimicrobial therapy.
CHANGES IN DRUG DISPOSITION
Disposition is the term used to describe
the simultaneous effects of distribution and
elimination, that is, the processes that occur subsequent to absorption of the drug.
Even though therapeutic agents are used
predominantly in diseased patients, there
are relatively few studies of the influence
of disease conditions on drug disposition
and dosage.
The disposition kinetics of a drug can be
influenced by the capacity of the drug to
penetrate cellular barriers (determined by
a and lipid solubility), by the extent of
pK
binding to plasma proteins (mainly albumin) and extravascular tissue constituents,
by activity of drug-metabolizing enzymes
(which determines rates of major pathways
of metabolism), and by efficiency of excretion (mainly renal) mechanisms. Certain
physiological states (pregnancy, the neonatal period), prolonged fasting (48 h or
longer), some disease conditions (fever,
dehydration, chronic liver disease, renal
impairment), and certain types of drug interaction (plasma protein binding displacement, inhibition of drug metabolic pathways or competition for carrier-mediated
excretion processes) may alter the disposition of drugs.
Attempts to correlate changes in dispo(especially hepatic clearance) of
that
undergo extensive metabolism
drugs
sition
with various liver function tests have been
generally unsuccessful. In chronic liver disease, serum albumin concentration might
serve as a prognostic indicator of hepatic
drug-metabolizing activity. The clearances
of indocyanine green and antipyrine provide quantitative assessment of different
aspects of liver function (Branch et al,
1976). Indocyanine green (which is excreted unchanged in bile) can be used as a
marker substance to indicate carriermediated hepatic uptake (hepatobiliary
transport) and liver blood flow, while antipyrine measures hepatic microsomal oxidative activity. Since antipyrine has a low
hepatic extraction ratio, it is not a useful
marker substance for metabolism (intrinsic
hepatic clearance) of drugs with clearances that are highly dependent upon liver
blood flow (such as isoproterenol, lido-
caine, morphine).
Unlike the poorly quantifiable situation
associated with liver disease, endogenous
creatinine clearance can be used to estimate decreases in renal function (glomerular filtration). Calculation of altered renal
clearance of a drug is based on the fraction of normal renal function that is present
in the patient and requires knowledge of
the fraction of dose usually excreted unchanged in the urine. The altered clearance can be used to make adjustments in
the dosing rate.
Although infectious diseases have in
common the presence of fever, the changes that occur in drug disposition will vary
with the pathophysiology of the disease
condition. Alteration in the volume of distribution with concomitant change in plasma
drug concentrations appears to occur most
often, while the half-life may or may not be
affected. These variations in altered pharmacokinetic behavior lead to uncertainty in
predicting dosage adjustments that may
be required. The use of combined drug
therapy, particularly when the possibility of
drug interaction exists, would further complicate understanding the altered pharmacokinetic-pharmacodynamic relationship.
INTERPRETATION OF ALTERED
DISPOSITION
The
ability to interpret alterations in drug
disposition requires an understanding of
the interrelationship among the various
pharmacokinetic parameters and the basis
of their calculation.
The time course of drug in the body depends upon both the volume of distribution
and systemic clearance, while half-life reflects the relationship between these two
ance as
the
pharmacokinetic parameter
of
choice.
The volume of distribution at
state, unlike
steady
of
in the rate constant for drug elimination. As the elimination rate constant decreases, Vd!area) approaches )
ss The
{
d
V
’
volume of distribution at steady state represents the volume in which a drug would
appear to be distributed during steady
state if the drug existed throughout that
volume at the same concentration as in the
plasma. This term is the proportionality
constant between the amount of drug in
the body and the plasma concentration at
steady state. It can be calculated by the
use of areas (Benet and Galeazzi, 1979):
changes
(.
d
V
)
rea
is independent
parameters:
Altered disposition can be due to changes
in either or both of the basic parameters,
volume of distribution and clearance; thus
half-life (which is a derived pharmacokinetic term) will not necessarily reflect an anticipated change in drug elimination (table
IV). Interspecies comparisons of drug metabolism rates should use intrinsic clear-
where AUMC is the area under the first
moment of the plasma concentration-time
curve, that is, the area under the curve of
the product of time and plasma concentration over the time span zero to infinity. The
significance of AUMC lies in the fact that
the fraction AUMClAUC is equal to the average time a drug resides in the body. This
value is generally called the mean residence time (MRT), which is the time when
63.2% (1.44 x half-life) of an intravenous
dose has been eliminated.
Fever induced by E coli endotoxin produced changes in pharmacokinetic parameters similar to those seen in IBR virus infection (Abdullah and Baggot, 1986). In
each disease condition, statistically significant corresponding changes occurred in
the steady-state volume of distribution and
systemic clearance of the drug, while the
half-life remained unchanged. It follows
that half-life alone is not a reliable indicator
of changes in drug disposition induced by
disease conditions.
in drug binding to plasma proteins or extravascular tissue constituents
or in the relative volume of body fluid compartments could alter the volume of distribution. By affecting the drug concentrations in the plasma and more importantly
at the site of action, the altered volume of
distribution could change the dose-effect
cokinetic behavior may occur in some disease conditions. An increased sensitivity to
the pharmacological effects of certain
drugs may occur and could be the result of
functional or morphological modification of
the drug receptors, or interaction with substances retained in animals with renal dysfunction. The anesthesia-inducing dose of
thiopental, for example, is substantially
lower in uremic animals. This could be
partly attributed to decreased protein bind-
ing.
Change
relationship.
Alterations in the clearance of
drugs
that are eliminated mainly by renal excretion unchanged in the urine can be estimated from the decrease in renal function
(based on endogenous creatinine clearance).
Although various types of liver disease
can alter the disposition (clearance and/or
volume of distribution) of a number of
drugs (antipyrine, lidocaine, propranolol,
diazepam) or increase the concentration of
free (unbound) drug in the plasma (due to
hypoalbuminemia), it is not possible to predict the changes that will occur in pharmacokinetic behavior of a drug or how they
may affect the dose-effect relationship.
The detailed study of the disposition of certain indicator (test) substances in the various types and stages of liver disease appears
to
offer
the
most
promising
approach.
in
related
Changes
that
are
pharmacodynamic activity
only indirectly to pharma-
COMBINED PHARMACOKINETICPHARMACODYNAMIC MODELING
and
nonSeveral
compartmental
compartmental approaches have been
successfully applied to the combined pharmacokinetic-pharmacodynamic modeling
of various drugs (Colburn, 1981; 1987).
For many drug classes the pharmacological effects produced correlate well with the
plasma drug concentrations. This situation
applies when the effects are direct and im-
mediate, which infers that the concentrations at the site of action and in the plasma
are essentially in equilibrium. When pharmacological effects are not directly related
to plasma drug concentrations, the complexity of the relationship is determined by
the extent of separation between the observed effect and the plasma concentrations measured. Dissociation can be attributed to the drug exerting an indirect effect,
to redistribution or delayed access to the
site of action, or be due to the character of
the drug-receptor interaction. It is only
through the further development and evaluation of combined pharmacokinetic-
pharmacodynamic modeling techniques
complex dose-effect relationships can be elucidated.
that such
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