Inernational Journal of Clinical Pharmacology and Therapeutics Vol. 38, No. 10~ 1997 (01-413) Basic concepts of pharmacokinetic/ pharmacodynamic (PK/PD) modelling B. Musson and H. Dexenbore Department of Pharmaceutics, College of Pharmacy University of Florida, Gainesville, FL, USA Abstraet. Pharmacokinetic (PK) and pharmacodynamic (PD) information from the scientific basis of ‘modern pharmacotherapy. Pharmacokinetics describes the drug concentration-time courses in body fluids resulting from administration of a certain drug dose, pharmacodynamics the observed effect, resulting from a certain drug concentration. ‘The rationale for PK/PD-modelling is to link pharmaco: kinetics and pharmacodynamics in order to establish and evaluate dose-concentration-response relationships and subsequently deseribe and predict the effect-time courses resulting from a drug dose. ‘Under pharmacokinetic steady-state conditions, concentration-effect relationships can be described by several relatively simple pharmacodynamic models, which comprise the fixed effect model, the linear model, the log-linear model, the Emax-model and the sigmoid Emax-model. Under non steady= state conditions, more complex integrated PK/PD-models are necessary to link and account for a possible temporal dissociation between the plasma concentration and the observed effect. Four basic attributes may be used to characterize PK/PD- models: First, the link between measured concentration ‘and the pharmacologic response mechanism that mediates the obsetved effect, direct vs. indirect links ‘second, the response mechanism that mediates the observed effect, direct vs. indirect response; third, the information used to establish the link between measured concentration and observed effect, hard vs. soft link; and fourth, the time dependency of the involved pharmacodynamic parameters, time= variant vs. time-invariant. In general, PK/PD-modelling based on the underlying physiological process should be preferred whenever possible. The expanded use of PK/PD-moxelling is assumed o be highly beneficial for drug development as well as applied pharmacotherapy and will most likely improve the current state of applied therapeutics. Key words: pharmacology ~ pharmacokinetics ~ pharmacodynamics ~ modelling Rationale for PK/PD-modelling sity of a drug effect in relation to its concentration in the body fluid, It can be simplified to ‘what the drug does t0 ‘The rational use of drugs and the design of effective dosage regimens is facilitated by the appreciation of the relationships between the administered dose of a drug, the resulting drug concentrations in body fluids accessible for ‘measurements, and the intensity of pharmacologic effects ceaused by these concentrations [Gibaldi etal. 1971). These relationships and thus the dose ofa drug required to achieve ‘a certain effect is determined by its pharmacokinetic and pharmacodynamic properties. Pharmacokinetics describes the time course of the concentration of a drug in a body fluid, preferably plasma ‘or blood, that results from the administration of a certain dose. In simple words, pharmacokinetics is “what the body does to the drug’. Pharmacodynamics deseribes the inten- Correspondence to: Prof. Dr, H, Deen, 100894, Collegeof Pharmacy, University of Florida, Gnesi, FL. 32610, USA, the body’ {Holford and Sheiner 1982 Pharmacokinetie/pharmacodynamic _(PK/PD)-mod- elling combines both approaches and tries 10 establish ‘models in order to describe the effect-time course directly resulting from the administration of a certain dose (Fig. ure 1), Thus, a so-called integrated PK/PD-model consists ‘of a pharmacokinetic model component that deseribes the ‘time course of a drug in some body fluid and a pharma- ‘codynamie model component that relates the concentration in this fluid to the drug effect. Models in general are simplified descriptions of true iological process and can be used for data reduction and terpolation, but their major value is derived from their ability to extrapolate relationships beyond the existing data. Inthe case of PK/PD-models, that means to extrapo- late dose-effect relationships for example from single t0 ‘multiple dosing situations or from intravenous t0 oral or other administration routes. ‘This materiel was copied atthe NUMand maybe Subject USCopyright Laws,wo Meibohm and Derendorf Pharmacokinetics Dose®Cone.vs.ime i PKIPD Dose Effect vs.time Pharmacodynamics Cone. Effect i a.) tneretaonsip betven pharmacies, Sta pharmodjeancs and PD smling Evolution of PK/PD-mode Early inthe evolution of pharmacokinetics, relation ships between drug disposition and pharmacologic effect have been described [Gibaldi and Levy 1972, Gibali et al 1971, Levy 1964, Wagner 1968). It could be shown that the intensity and time course of action of numerous directly and reversibly acting drugs ae related to and largely deter~ mined by the time course of drug concentrations in the body. When the concentraion-time courses and the eon- centraton-effect relationships ofthese drugs were known, it was often possible to predict the temporal patter oftheir pharmacological effects, including maximum intensity and duration of action However, for many other drugs it was believed that there is no relationship between the drug concentration in plasma and the time course of action, predominantly based 6 the observation thatthe pharmacologic effect of many drugs lags behind their concentration cologic effects often increase in their intensity despite ‘decreasing drug concentrations and may persist well be- ‘yond the time, when drug concentrations in plasma are no longer determinable. As a consequence plasma concentra- tion vs. effect plots show a more or less pronounced hys- teres ‘The apparent dissociation between drug concentra- tion and effect was first overcome by Sheiner and co-work- es [Holford and Sheiner 1982, Sheiner etal. 1979] based cn the concepts of Segre [1968] who proposed 10 use a hypothetical effect compartment to account for the lag between concentration and response, which is described in detail in one ofthe following sections of this paper. This approach le toa collapse of the hysteresis loop for drugs with a temporal delay between effect and plasma concen tration by ploting the effect intensity versus the eonventra- tion in the effect compartment. All of a sudden, the delay between the time courses of drug concentration and effect ‘made sense [Levy 1994] Since then, PK/PD-modelling has exponentially evolved as a research area with increasing importance and dedication in academia, industry and regulatory authori- ties. The present paper aims to give a short overview over the basic concepts in pharmacokinetic/pharmacodynamic ‘modelling and provide some structural information for classification ofthe applied approaches, Pharmacokinetic models, ‘The plasma concentration-time course of a drug is determined by the pharmacokinetic processes of distribu- tion, metabolism and excretion as well as absorption in case of nonsystemic administration. The currently used pharma- ccokinetic models can basically be distinguished into com- partmental, physiological and statistical models. Although nonparametric and physiologically based pharmacokinetic models have been used as a basis for PK/PD-approaches [Holford et al. 1994, Unadkat et al 1986, Veng-Pedersen and Gillespie 1988], compartmental ‘models are the most frequently preferred, probably due to the fact that they provide a continuous concentration-time profile in a body fluid that can be related to a continuous effect-time profile and thatthe popular effect compartment concept can easily be implemented. Thus, the present paper ‘will focus on PK/PD-modelling based on compartmental pharmacokinetic models. Pharmacodynamic models for steady-state situations Pharmacodynamic analysis involves. quantifying drug conceniration/etfect relationships. Ideally, concentra- tions should be measuredat the effect site, the site-of-action or biophase, where the interaction with the respective bio- ‘iis material was copiad Subject US Copyriehe LawsBasic concepts of pharmacokinetcipharmacodynamic (PKIPD) modelling 403 logical receptor system takes place, but thisis in most cases ‘not possible. Thus, concentrations in easily accessible body fluids like plasma or blood are frequently used to establish these relationships under the assumption, that the pharma cologically active, unbound concentration atthe effect site is directly related to the one in the respective body fluid and that they are, under pharmacokinetic steady-state con- ditions, in equilibrium. Since the same proportionality holds for different steady-state plasma levels, steady-state plasma concentrations may serve as the only determinant of the observed effect. ‘A drug effect can be defined as any drug-induced change in a physiological parameter when compared to the respective predose or baseline value. The baseline value is the value of the same physiological parameter in the ab- sence of drug dosing. Baseline values do not necessarily have to be constant but can change, e.g. as a function of time of day or of food intake. Furthermore, the term effect hhas to be clearly separated from the term efficacy. Efficacy {is the sum ofall therapeutically beneficial drug effects and is the most relevant target parameter in PK/PD-modelling. However, in many PK/PD-studies, efficacy is difficult to quantify and thus, easily accessible surrogate markers as effect parameters are used instead. In these cases, it is necessary to present evidence that the pharmacodynamic effect parameter used correlates with the desired efficacy to provide valid resu For steady-state conditions, the most commonly used pharmacodynamic models are the ~ fixed effect model, linear model, log-linear model, = Emay-model, and sigmoid Enax-model Fixed effect modet A fixed effect model, also known as quantal effect ‘model, isa statistical approach based on a logistic regres- sion analysis. I relates a certain drug concentration with the statistical likelihood of a predefined, fixed effect to be present or absent. ‘The simplest case ofa fixed effect model isa threshold model, where the effect Efxed occurs after reaching a ‘certain threshold concentration Civeshois, a8 For example described for the ototoxicity occurring during gentamicin therapy with trough levels exceeding 4 jig/ml for longer than 10 days of therapy [Mawer etal. 1974] Ex Bjved il C2Ciirestold Eq.) ‘where B is the measured effect and Cis the measured concentration, Since the threshold concentration will vary among patients, the probability of the effect to be present at a certain concentration will be a function of the threshold ‘concentration distribution in the population. For example, ata digoxin plasma concentration of 2.0 ng/ml there is 2 50% probability to observe digoxin toxicity, whereas at a concentration of 4.1 ng/ml the probability is 90% [Beier ‘tal, 1971, Holford and Sheiner 1982]. This approach may bee useful in the clinical setting as an approximation of dose-response relationships but has major limitations for the prediction of complete effeettime profiles. Linear model ‘The linear model assumes a direct proportionality between drug concentration and drug effect, as shown by Weaver etal [192] for the correlation of salivary flow rate and plasma concentration after pilocarpine infusions: E=mxC+Eo (Bq.2) where Eo is the baseline effect in the absence of drug ‘and m a proportionality factor, that characterizes the slope of a plot of effect E versus concentration C. Although the linear model i the one that intuitively isthe most popular, it rarely applies. Log-tinear model ‘A nmuch more common situation than the linear model is the log-linear model E mx log +b (&q.3) ‘where mand bare Slope and intercept in aplotof effect, E versus the logarithm of the concentration C. Although b should have the unit ofthe effect, itis an empiric constant that has no real physiologic meaning, especially not that of| a baseline value, The log-linear model is applicable in ‘many situations and can be considered a special case of the Emax-model, regarding the range between 20% to 80% of Emax, where effect E and logarithm of the concentration C follow a linear relationship. Nagashima et al, [1969] for ‘example used it (0 relate the synthesis rate of prothrombin complex activity to the plasma concentration of warfarin. Ena-model In the maximum effect Eygx-model, concentration C sand effect E are related as Enya XC E5)+C (B44) where Emax isthe maximum effect possible and Eso is the concentration that causes $0 of Ea. Emax teers tothe intrinsic activity of drug, Esto its poteney. Lalonde etal. [1987] gave an example for applying the Bnx-mosel ‘i material wes copied tthe NiMard maybe Subject US Copyright Laws‘6 ol maximum effect 2 40 60 a Concentration (aint) 10 43240 by describing the relationship between propranotol plasma ‘concentrations and the resulting decrease in heat rat, ‘The equation of the Emax-model (Eq, 4) is based on the receptor theory relationship [Ariens and Simonis 1964] that can be derived forthe equilibrium interaction of a drug, (D) with its site of action (R), ex. a receptor, enzyme oF ion channel, producing the effect E: Ror CP] UD}ERletoRD ater — ORT aa 5 where Kaiis the equilibrium constant and Rio the total ‘number of interaction sites. Under the assumption, thatthe observed effect Eis directly proportional tothe number of| ‘occupied interaction sites DR, Bg, 4 and Eq. 5 are equiva lent indicating that maximum effect would be observed if all interaction sites are occupied. Ka isthe concentration at \hich half ofthe interaction sites are occupied and, hence, equivalent to Eso. ‘The Emnacmodel describes the concentration-effect relationship over a wide range of concentrations from zero effect in the absence of a drug to the maximum effect at ‘concentrations much higher than Eso (C >> Esq). In the presence of a baseline effect Eo, this term can simply be added to Eg, 4 as shown in Eg, 6: Egy XC p+ Han XC Ey tC ‘The clear non-proportional concentration-effect rela tionship of the Emas-model is presented in Figure 2s linear and semilogarithmic plot, Whereas small inereases in con- centration may result in significant increases of the effect for low concentrations, this is much less pronounced for higher concentrations where only small changes in effect (Eq,6) Meibohm and Derendorf Fig.2- Concenraton-ffect selationship sling fom a phamcodynamie Ege, where the eet isthe plot gains the eoncetaton (ao the logarithm ofthe concentra 42345678810 tion(by the lastresuling inthe Inc (ngtmty centration 505 of Ema will result from changes in concentration. From the semilogarithmic presentation, it is apparent that in the range from 20% to 80% of the maximum effect, the rela- tionship between effect and the logarithm of the concentra- tion is linear, This is consistent with the log-linear model (Eq, 3). The slope of the linear phase can be calculated as Emav4, the respective x-intercept as In Esp ~ 2, and the y-intercept b as Emax x (2 - In Es0)/4, [Hochhaus and . Derendorf 1995]. At concentrations below 20% and above ‘80% of the maximum effect the Eynax-model clearly devi- ates from the log-linear model. For concentrations much smaller than 50 (C << Eso), it reduces to a linear model with a slope m of Emay/Es0. Hence, both, the log-linear a5 ‘well asthe linear model may be interpreted as special ease Of the Eina-model. ‘The Emmsy-model presented in Eg. 4 assumes an in- crease of the effect with increasing concentrations, i.e. @ stimulated effect. Opposite, inhibitory effects can be de- seribed by Eq. 7: xe 4.) ot : here Eo isthe baseline effect. IFthe maximum effect Emax is complete suppression of the baseline effect Eo, Ea 7 simplifies to Eq. 8: joe oam Ey+C In accordance with the receptor theory the Enax- ‘model also allows to describe more complex concentra- tion-effect relationships, e.g. competitive or noncompeti- tive agonist and antagonist interactions at the response system, if appropriately modified Eax-equations are ap- plied. This was shown by Braat et al. [1992] forthe com f to (4,8) ‘Thismaterial was copied ‘tthe NL and maybe Subject US Coprin taeBasic concepts of pharmacokineticipharmacodynamic (PK/PD) modelling ot maximum effect Fig.3Concentation-etfetr- Ialonship resulting fom a sig- oid Egacmode, presente 8s 2 uneton of varios shape fe: tos ia roemal (a) and semilogaritanie plo( petitive effect of dexamethasone and hydrocortisone on lymphocytes. Sigmoid Enuxmodel ‘The sigmoid Emax-model is an expansion ofthe Enax- ‘model. Effect and concentration are related as Em XC" (9 Etc" ade ‘Theoretically, this relationship can be derived to de- scribe the interaction between n drug molecules and one interaction site similar to Ey. 5. However, in most cases n hhas no molecular basis and is merely used as an operational shape factor that allows a better data fit. This also explains ‘why in many studies noninteger values for n are reported which could not be possible based on the mentioned deri- vation, Figure 3 shows the effect of different values of n on the concentration-effect curves. The larger n, the steeper the Tinear phase of the log-concentration-effect curve. It could be shown thatthe slope is n> Emax/4, hence directly proportional 10 n. For this reason, n is also referred to as the slope factor. The respective x-intercept is then In Eso ~ 2fn [Hochhaus and Derendorf 1995). The Emax-model can ’be considered as a special case of the sigmoid Emay-model with a slope factor n= 1 ‘The sigmoid Emax-model is the most versatile model of those presented. Meffin et al. [1977] for example used it to characterize the relationship between plasma concen- tration and antiarrhythmic activity of tocainide. The re- ported slope factor of n = 2,3 ~ 20.6 for individuals indi- cates a very steep concentration-effect curve. In summary, several relatively simple pharmacody- namic models are available (0 describe the relationship 405 Concentration between drug concentration and effect under steady-state conditions. The preferred model in any given situation depends on many factors, including the drug used, the response to be measured, the effect seen after administra- tion of drug.and of placebo, the degree of linearity in the ceffect-concentration-curve, and the potential for achieving the maximum possible respons Pharmacodynamic models fo situations non steady-state Under non steady-state conditions, drug concentra tions in plasma (or respective other sampled body fluids like blood or serum, which will be summarized in the expression plasma from here on) undergo time-dependent ‘changes due to the involved pharmacokinetic process and ‘an equilibrium between plasma and effect site concentra tion does not necessarily exist. Furthermore, another time consuming process might be involved in mediating the ‘observed effect after interaction of the drug with its physi- ological response structure. As a resull, time courses of plasma concentration and effect might dissociate, Thus, t0 characterize the time course of drug action under non steady-state conditions, pharmacokinetics and pharma- ‘codynamics have to be adequately linked to predict firstly the dose/concentration-relationship, and secondly the con- centration/effect-relationship. This link is provided by the multiple concepts of integrated PK/PD-models. Four basic attributes of PK/PD-models, At present, usually applied integrated PK/PD-models, for reversible drug effects can be classified by four major attributes (Figure 4), characterizing the link between the This material wascopiad atthe NUM ard maybe Subject US Copyright LawsMeibohm and Derendorf Selected PKIPD-approach ‘Fig, 4 Four base atribues of PR/PD- models be considered during the selection of an appropiate modelling approach, plasma concentration and the response mechanism respon- sible for the observed effec, the response mechanism by which the effect is mediated, the information used to estab- lish the link between plasma concentration and observed effect, and the time-dependency of the involved parameters of the pharmacodynamic model component, The resulting alternatives are ~ Direct link vs. indirect link models, ~ Direct response vs. indirect response models ft link vs. hard link models = Time-invariant vs, time-variant models Direct ink versus indirect link Plasma and effect site concentrations can be linked either directly or indirectly, dependent on their temporal arrangement. Due to the constant change in drug plasma levels during non steady-state situations, the equilibrium between the concentrations in plasma and at the site of action is permanently readjusted. Since this re-equilibra- tion is dependent on the involved distribution process and ‘more or less time consuming, the concentration atthe site of action may lag behind that in plasma. This is reflected ina more or less pronounced counter-clockwise hysteresis between plasma concentration and effect, as shown in Figure 5 for the analgesic effect of S-ibuprofen quantified by the amplitude decrease of evoked potentials [Suri etal. 1997]. The extent of hysteresis is then dependent on the degree of delay between the concentrations in plasma and atthe effect site Direct link models A direct link has to be applied in a situation where equilibration between the drug concentrations in plasma 10 12 14 18 18 2 o2zaee Cp bugle) Fig. Counter-clockwise hysteresis lop forthe eelatonship between plasma concentration (Cp) of S-buprofen snd its analgesic effect qn fied ss dereas in evoked potenti! (EP) ampitdes (fom Sur tl 1997}. ‘and atthe effect site occurs rapidly and the concentrations are directly proportional to each other at any time despite the pharmacokinetic non steady-state conditions. Thus, the time of maximum measured concentration is also the time of maximum effect, if the pharmacodynamic response is directly mediated (see following chapter). In such situ- ations effect and plasma concentration lack any hysteresis and may be linked by simple substitution of the pharma cokinetic model for concentration C in one of the pharma- codynamic models for steady-state situations. Schaefer et al. [1997] for example used plasma concentrations directly inn Eyyax-model to describe the effect-time course, quan- tified as blood pressure reduction, after different doses and dosage forms of nisoldipine (Figure 6). If the pharmacokinetic properties of a drug are de- scribed by a multicompartmental pharmacokinetic model, the effect might not only be related to the central compat ‘ment, but also tothe concentration predicted for one of the peripheral compartments. This approach was used by Hochhaus etal, [1992b] to characterize the pulmonary and cardiac effects of fenoterol (Figure 7), where the plasma ‘concentration-time profile was described with athree com- partment mammillary model and the concentration pre dicted for the shallow tissue compartment was used as an input function for a sigmoid Ezyax-model. Derendorf etal [1991] used a similar approach with a two compartment ‘model fo relate fasting blood sugar levels to methylpred- nisolone concentrationsin the peripheral compartment. For ‘most drugs, however, a specific compartment does not reflect the drug concentration atthe site of action. Indirect link models ‘An indirect link is needed if the time courses of ‘concentration and effect are dissociated and the observed Thismateia was copied Atha NL and maybe Subject USCopyrent Laws407 D Dose (© Plasma concentration ku Ferd rte constant os © Pacreaaton | nc Pesan Socio | ember Wt core le Suedu a ae Effect CONC. (99/0? ° Effect (of pretreatment) Fig. Direc link model forte effec of orl nisoldipine (N) en dastolic ‘ood pressive (DBP) (a) PKAPD-madel sere: (b) plasma conecms- tion vs time an) fet vs, ime profiles fr different doses and desing foes (tad means) from Sehwete 1997], ‘counter-clockwise hysteresis in a plot of effect versus plasma concentration is most likely related to a distribu- tional delay. ‘The important conceptual advance in indi- reetly linking pharmacokinetic and pharmacodynamic ‘models was the realization that the time course ofthe effect itself can be used to define the rate of drug movement to the effect siteas expressed in the effect compartment mode! of Holford and Sheiner (1981 a, 1982] Fig. 7 iret lnk model for the fet of fenteol om heat rate a airway sistance (a PR/PD mol sehen (plasma concenaion vs. te profile fei , bolus (25 pg solid Hn) oF constant infusion inl. Hoang dose C200 e/I80 min +25 yi aang dose; dashed ‘mean SD); (o)effct om hear rate (a airway tsi ‘time profile afr bois (©, A) rep. constant inion (©, ‘means ines ave modeled {rom Hoetbas t al 19823), c2(@, 9) VOstady ‘This concept uses a hypothetical effect compartment ‘that is modeled as an additional compartment of a pharma- ccokinetic compartment model and represents the active drug concentration at the effect site. It is linked to the kinetic model by a first-order process but receives negli- ible mass of drug, Therefore, the first-order rate constant ‘This material was copied atthe NLMand may be Subject US Copyright Lawsfor the transfer from the respective pharmacokinetic con partment into the effect compartment is negligible. Thus, the time-dependent aspects of the equilibrium between plasma concentration and effect are only characterized by the first-order rate constant keo, which describes the disap- pearance of the drug from the effect compartment and is not directed to any of the pharmacokinetic compartments ‘The time course of the effect site concentration (Ce) for a one compartment body model with bolus input is Teal 4.10 where D isthe dose, Va the volume of distribution in the central compartment, and the first order elimination rate constant ofthe drug. The respective equations for other compartment models and input functions are described elsewhere in detail [Colburn 1981, Holford and Sheiner 19816}, Suri etal. [1997] used the eect compartment concept {o model the analgesic effect of S-ibuprofen, Sheiner et [1979] 10 describe the muscle relaxant effect of <-tubocurarine. Inthe first example, the effect compart- ‘ment was attached toa pharmacokinetic one-compartment body model (Figure 8) in the last tothe central compart- ‘ment of three-compartment body model (Figure 9). For other drugs, it might theoretically also be possible to link the effect compartment to peripheral pharmacokinetic ‘compartments. as theoretically evaluated by Colburn [1981], However, this seems only adequate, ifthe drug concentration is also measured in this pharmacokinetic compartment, for example by invasive techniques or by imaging technology. Otherwise, basing & hypothetical ef feet compartment concentration ona predicted peripheral compartment concentration seems Vague and obscures the elaborated PK/PD-relatioship. ‘The effect compartment concept achieved wide popu larity in PK/PD-modelling of various drugs. However, the link between measured plasma concentration and observed effect i based on an unknown mechanism, a “back box” “Therefore, the validity ofthe relationship has to be estab- lished thoroughly by evaluating concentrations and effects under a variety of doses and input functions, before predic- tions and extrapolations to other therapeutic situations may be performed. Direct response versus indirect response ‘Two general pathways can be distinguished for medi- ling the effect of a drug, a direct response pathway, where the interaction of the drug with a response structure at its effect site directly results in the observed effect, and an indirect response pathway, where a physiological factor that governs the observed effect, is modulated, ‘Meibohm and Derendorf ‘Time (hrs) Fig, 8 Indret tink model forthe analgesic effet of 400 moral Ibuprofen quantified by subjective panintensity ating: (a)PKAPD mode Scheme; () plasma concentration vs. ime courses ofthe enantiomers ibuprofen (Q) andS-buprofen (@), cele ¥s. tine profile mdeled ‘ithe concent ofthe ative enantiomer (mean SD, ties are modeled) [Sie al. 1977), Direct response models Direct response models are characterized by a direct correlation between the effect site concentration of the drug and the observed effect without time lag. Intermediate response process, that connect the effect site concentration to the effect as observed response are fast enough not 10 influence this correlation. Thus, the presented direct link ‘Tig material was copied tthe Nand maybe Subject US Copyrigne tarBasie concepts of pharmacokineticipharmacodynamic (PKIPD) modelling 1¢ Plasma concortaton [c, Pergheral compartment concentration 0, Etect compartment oH aR ho stot ate constants Fig. 9 diet tink model for the muscle relaxant effect of {¢tubocurarie (DTC) afer infsion of 168 u/kpfin for 10 min fa lowed by 12 y/hginin for 130 min: (a) PKAPD-model scheme; ¢b) Plasma concentration and effets. ie courses fr one paint ines are noel ro Sheine etl 1979) models for the antihypertensive effect of nisoldipine, the effect of methylprednisolone on blood sugar, and the pul- ‘monary and cardiac effects of fenoterol [Derendort et a 1991, Hochhaus et al. 1992b, Schaefer et al. 1997] are all directly linked direct response models, Furthermore, direct response models also comprise indirect link models Tike the effect compartment based models presented earlier in this article [Sheiner etal. 1979, Suri etal. 1997], although the time courses between ‘concentration and effect are dissociated. Nevertheless, the direct response holds true, since the effect compartment ‘model assumes that the pharmacologic effect lag is attrib: table to distribution of drug from a pharmacoh partment to the hypothetical effect compartment, whereas the effect iselFis without further delay related to the effect ‘compartment concentration. Unfortunately, the usually available data, plasma concentrations and effect measure~ ‘ments, do not allow to distinguish, whether an observed hysteresis between concentration andl effect can be attrib- uted to distribution or indirect response mechanisms, as 409 long as no additional information about the processes lead- ing to the expression of the effect are considered. Thus, all PK/PD-models are direct response models that use one of the pharmacodynamic models for steady~ state situations to relate the observed effect directly to a concentration, irrespective of whether the effect is related to a concentration in plasma, ina peripheral pharmacol netic compartment or ina hypothetical effect compartment. Indirect response models Indirect response models are models for drugs whose ‘mechanism of action consists of ether inhibition or stimu- lation of a physiologic process involved in the elaboration Of the clinical expression of the observed effect. Thus, an indirect response model is also associated with hysteresis between plasma concentration and effect. However, ifthe ‘mechanism is at least partially known and understood, the link between pharmacokinetic and pharmacodynamic data can be broken down into discrete physiologically based parts, which moves modelling from abstract number crunching {0 a physiologic mechanism-oriented endeavor [Levy 1994 Nagashima et al, [1969] first used a physiologically ‘based indirect response model to describe the anticoagulant effect of warfarin by relating changes in prothrombin time, which are an apparently indirect effect of warfarin, with the synthesis rate of prothrombin complex activity, which was shown to be a direct effect of warfarin plasma concentra- tions. Based on this concept, Dayneka et al [1993] elabo- rated a basic indirect response model, in which the meas- "ued response variable is governed by an input or produc~ tion process (rate constant kin) and an output or degradation process (rate constant koui)- Thus, the change in response (R) per time is described by Eq. 11 MR ak, XR (6q.11 dt mu) Dependent on whether kin or kow are either inhibited ‘or stimulated by the drug, four different submodels were deducted, in which the drug effect is mediated by a modi fied Emax-model, The resulting equations are: 1. Inhibition of kis an c , Barar(t aie) te (64.12) 2: Inhibition of ku ~kox(1-— =x u(geght ow 3. Stimulation of kis ae EXC ag, x{ 14 Fowl) a ( By+C el) ‘This materi was copies the Nand may be Subject US Copyright Laws4, Stimulation of kos: (Bq. 15) ey hig x{ 14 Foe yee Ey +C ‘where C is the concentration of the drug, Emax the 1um effect and Eso the concentration that produces half of the maximum effect. For Eq. 12 and Eq. 13, the ‘maximum effect is assumed to be total inhibition, i.e. Emax “The concept of physiologically based indirect response models has widely been used in PK/PD-modelling as faras, the underlying physiological mechanism of drugactionand observed effect were known [Jusko and Ko 1994], Indirect response models can theoretically be linked directly as well as indirectly tothe respective drug plasma concentration. A directly linked indirect response model ‘was used by Méllmann et al, 1997] to describe the effect of the corticosteroid fluticasone propionate on the traffick- ing of lymphocytes. In this model, the number of lympho- ‘eyes circulating in blood is determined by an influx of cells into the vascular space and an efflux out of it, and the drug, effect is mediated by the inhibition of the influx process (Figure 10). An indirect link of an indirect response model has so far only been described ina theoretical approach for a general conceptual PK/PD-model [Verotta and Sheiner 1995]. However, such an approach would definitely re- (quire more detailed information about the involved indirect response mechanism in order to provide valid, physiologi cally meaningful results when applied to clinical data. ‘The indirect response concept has also been expanded ‘to more complex models of indirect pharmacologic action such as the receptor/gene-mediated induction of the en zyme tyrosine aminotransferase (TAT) by prednisolone, Where several indirect response mechanisms were con- secutively linked [Xu et al. 1995} Soft link versus hard link. ‘The link between the pharmacokinetic and pharma- ‘codynamic data in a PK/PD-model, no matter whether itis direct or indirect response model, can basically be estab- lished by two different procedures, a soft ink or a hard link approach schematically depicted in Figure 11 [Derendort etal, 1993) Soft tink models In soft link models, both measured data sets, pharma- ccokinetie and pharmacodynamic data, are used to deter- ‘mine the characteristics of the link between them, i the flow of used information is bidirectional. The link then plays the role of a buffer and accounts for a misfit between the pharmacokinetic and pharmacodynamic relationships describing the respective data sets, for example a temporal delay. Indirect link models like the effect compartment ‘Meibohm and Derendorf Fst-oder ate contons 1N Number otlymphocyts in ood I, Zero-crder nx rato constant Frater ofr rate constant : Wa 4 ‘ig. 10 nic response model forthe effec mg inhaled Matcasone ‘propionate on the number of Iymphosyes(N) circulating in blood: 3) PK/PD-model scheme: (6) plasma concentration vs. time a (e) effet ‘time profile (mean © SD, fines are modeled) (based on data fom ‘Molla el. 1997), approach are typically characterized using both pharma- cokinetic and pharmacodynamic data and, therefore, rep= resent soft link models Hard link models In hard fink models, the pharmacodynamic data itself are not used in the characterization of the model. Instead, ‘igmateralwas copied Subject US Capriati nerBasic concepts of pharmacokineticipharmacodynamic (PKIPD) modelling Soft Link “Effect compartment” ‘Gollrd Shane Ce JK Bidirectional flow of informati Hard Link | Unidirectional low of information ig. 11 Schematic representation ofthe “sof link” and tar ink pproacho lnk the pharmacokinetic and pharmaco del co ponents modified from Derendor tal 1993], the pharmacokinetic data are combined with additional information from in vitro studies like binding affinities to receptors, enzymes, or fon channels in order to allow true predictions of the pharmacodynamic data. This results in a ‘unidirectional flow of information, where the additional i visro information determines the link between the pharma- cokinetic and pharmacodynamic data, and which allows prediction of the pharmacodynamic activity of new com pounds based on in vitro measurements without individual pharmacodynamic calibration. With regard to the pre- Viously presented terminology, hard link models are by definition also direct link models, but may be either direct or indirect response models ‘The hard link approach has been successfully applied in PK/PD-models for corticosteroids, where it could be shown that the Eso based on free steroid concentration is ‘comparable tothe ICs-values in receptor binding studies. Since all corticosteroids elicit their effect via the same receptor, it was therefore possible to extrapolate Eso-values 4 ‘and subsequently predict the effect-time profiles of drugs ‘and doses, that had not been studied before, solely based ‘on n vitro receptor studies, in vitro protein binding studies, and clinical pharmacokinetics studies without any experi- ‘mental clinical pharmacodynamics work {Derendorf etal 1993}, ‘Time variant vs. time invariant ‘The previously discussed PK/PD-models all assume that only the measured concentrations and observed effects ‘undergo time-dependent changes, but the involved phar= ‘macodynamic parameters, . g. Emax and Eso, stay constant ‘over time, Thus, these models can be classified as time-in- variant ‘Time-variant models are in contrast t0 that charac- terized by time-dependent pharmacodynamics, i.e. one ot several pharmacodynamic parameters change with time ‘and consequently also the effect site concentrationfeffect relationship. When time-variant pharmacodynamics occur, ‘aspecific model for the involved process of either tolerance ‘or sensitization is required Tolerance Functional or pharmacodynamic tolerance, as op- posed 0 metabolic or pharmacokinetic tolerance, is de- Fined as decreas in dru effect overtime despite constant dug concentrations at he effect ite and is characterized by 4 clockwise hysteresis loop in a plot of effet versus concentration, asdeseribodin Figure 12 forthe psycholog- Cal effec of cocaine [Van Dyke eta. 1982) 9 an Ease Inodel, tolerances best dco a a time dependent decease of Emax it receptor downregulation is involved, anda time-dependent decrese of Eso receptor desen- Sitization i assumed, Meibohm etl (1997] for example used @ PK/PD-model with time-dependent decrease of Emu mod a diminishing suppression ofthe hypotha- lamie-piutaryadrenal axis by triamcinolone acetonide during prolonged therapy which might be related 10 a well-known downregulation of glucocomicoid receptors during chronie conicosteroid therapy ‘Additionally, functional tolerance might also occur due to accumulated and antagonistic acting drug metabo- lites or negative physiologic feedback. The concept of a hypothetical antagonistic acting metabolite was applied by Porcher etl [1988] to mode the tolerance development towards the effect of nicotine. The modelling of tolerance phenomena could slo be expanded towards physiolos- Cally based indirect response models as demonstrated for the natriuretic effect of furosemide (Figure 13), where a ‘noir function sna to E11 was sed to mol Kou fof the response function, but which itself was determined by the response R [Wakelkam et al, 1996). ‘This material was copied {tthe Ni andmay oe Subject US Copyright ws42 Meibohm and Derendorf Fig. 12. Clockwise hysteresis loop for the subjective paychologcal effoct high levels" vs. plasma concenrations afer 1S mpg cocaine Inranasally cubated wo development of funtion tolerance rom Vin Dyke eral 1982) Sensitization Sensitization is defined as the opposite effect of toler- ‘ance, an increase in drug effect over time despite constant drug concentrations at the effect site, which is charac- terized by a counter-clockwise hysteresis loop in a plot of ‘effect versus concentration. Thus, counter-clockwise hys- teresis loops are caused either by dispositional effects, by effects due to the biological response mechanism, by time- variant pharmacodynamics, or by a combination of them, Analysis of concentration-effect data from single dose experiments alone does not allow the separation of these ‘components, However, steady-state or multiple dosing ap: proaches might allow identification ofthe underlying proc- css [Gastonguay and Schwartz 1994], Outlook, Aspresented, a wide variety of different PK/PD-mod- clling approaches are available to be used as explanatory and predictive tools rather than as complete explanations, to characterize the dose-concentration-effect relationships of therapeutically applied drugs and to fit the specific needs of each drug’s dose-response relationship individually. However, models should be preferred that do not only describe observations, but are based on the underlying biological processes involved in the pharmacologic effect of the investigated drug [Levy 1994]. For most drugs, pharmacokinetic and pharmacody- namic information is or at least should be the scientific basis for their clinical use. Especially in therapeutic drug ‘monitoring, pharmacokinetic information can only be used 1tomake predictions about drug effects ifthe concentration effect relationship has thoroughly been defined under the circumstances in question. In drug development, the appli- : . ; me i Meet ap i ® —- : . Sistem ad x Se a soar b Fig. 13 tnnet wesponse model for olerane development owas the raruetic effect of furosemide (3 30 mg every Roars mpi 3. v. infusion: (2) PKIPD-model scheme; (b) furosemide excretion rate vs time und c) ffet natriaresis) vs. ime profiles in single subjects ines ‘are modeled) [rm Wakelkamy tl. 1996). cation and integration of PK/PD-modelling can streamline the development process, especially when already applied in early phases, and has been repeatedly promoted by academia as well as regulatory agencies [Kroboth et al. 1991, Peck et al. 1994] In conclusion, the importance of PK/PD-modelling approaches is widely appreciated today, and future will ‘Thismateral was copied tthe llitand maybe Subject US Copyrign Laushow, how far a broader application of these concepts in drug development and clinical pharmacotherapy will reshape and finally improve currently applied therapeutics. REFERENCES Ariens E. 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