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> HAL Id: hal-00901990 https://hal.archives-ouvertes.fr/hal-00901990 Submitted on 1 Jan 1990 HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. 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&horbar; pharmacokinetic-pharmacodynamic model Résumé&horbar; 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 REFERENCES Abdullah AS, Baggot JD (1986) Influence of induced disease states on the disposition kinetics of imidocarb in goats. J Vet Pharmacol Ther 9, 192-197 Baggot JD (1977) Principles of Drug Disposition in Domestic Animals: The Basis of Veterinary Clinical Pharmacology. Saunders, Phila- delphia Benet LZ, Galeazzi RL (1979) Noncompartmental determination of the steady state volume of distribution. J Pharm Sci 68, 1071-1074 Boxenbaum H (1980) Interspecies variation in liver weight, hepatic blood flow, and antipyrine intrinsic clearance: extrapolation of data to benzodiazepines and phenytoin. J Pharmacokinet Biopharm 2, 165-1766 Branch RA, James JA, Read AE (1976) The clearance of antipyrine and indocyanine green in normal subjects and in patients with chronic liver disease. Clin Pharmacol Ther 20, 81-89 (1981) Simultaneous pharmacokinetic/pharmacodynamic modeling. J Pharmacokinet Biopharm 9, 367-388 Colburn WA (1987) Pharmacokinetic/pharmacodynamic modeling: what it is. J Pharmacokinet Biopharm 15, 545-553 De Backer P, Braeckman R, Belpaire F, Debackere M (1980) Bioavailability and pharmacokinetics of phenylbutazone in the cow. Colburn WA J Vet Pharmacol Ther 3, 29-33 Eberhardson B, Olsson G, Appelgren LE, Jacobsson SO (1979) Pharmacokinetic studies of phenylbutazone in cattle. J Vet Pharmacol Ther2, 31-37 Errecalde JO, Button C, Baggot JD, Mulders MSG (1984) Pharmacokinetics and bioavailability of theophylline in horses. J Vet Pharmacol Ther7, 255-263 Ingvast-Larsson C, Paalzow G, Paalzow L, Ottosson T, Lindholm A, Appelgren LE (1985) Pharmacokinetic studies of theophylline in horses. J Vet Pharmacol Ther 8, 76-81 Martin K, Andersson L, Stridsberg M, Wiese B, Appelgren LE (1984) Plasma concentration, mammary excretion and side-effects of phenylbutazone after repeated oral administration in healthy cows. J Vet Pharmacol Ther7, 131-138 Mordenti J (1985) Pharmacokinetic scale-up: accurate prediction of human pharmacokinetic profiles from animal data. J Pharm Sci 74, 1097-1099 Schwinghammer TL, Kroboth PD (1988) Basic concepts in pharmacodynamic modeling. J Clin Pharmacol 28, 388-394 Miert ASJPAM (1989) Extrapolation of pharmacological and toxicological data based on metabolic weight. Arch Exp Vet Med 43, 481- van 488 Vesell ES, Lee CJ, Passananti GT, Shively CA (1973) Relationship between plasma antipyrine half-lives and hepatic microsomal drug metabolism in dogs. Pharmacology 10, 317328