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Review Incorporating Receptor Theory in Mechanism-Based Pharmacokinetic-Pharmacodynamic (PK-PD) Modeling

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Review Incorporating Receptor Theory in Mechanism-Based Pharmacokinetic-Pharmacodynamic (PK-PD) Modeling Drug Metab. Pharmacokinet. 24 (1): 3–15 (2009). Review Incorporating Receptor Theory in Mechanism-Based Pharmacokinetic-Pharmacodynamic (PK-PD) Modeling Bart A. PLOEGER1,3,*,PietH.vanderGRAAF2 and Meindert DANHOF1,3 1LAP&P Consultants BV, Leiden, The Netherlands 2Pfizer, Department of Pharmacokinetics, Dynamics, and Metabolism (PDM), Sandwich, United Kingdom 3Leiden-Amsterdam Center for Drug Research, Division of Pharmacology, University of Leiden, Leiden, The Netherlands Full text of this paper is available at http://www.jstage.jst.go.jp/browse/dmpk Summary: Pharmacokinetic-Pharmacodynamic (PK-PD) modeling helps to better understand drug efficacy and safety and has, therefore, become a powerful tool in the learning-confirming cycles of drug-development. In translational drug research, mechanism-based PK-PD modeling has been recognized as a tool for bringing forward early insights in drug efficacy and safety into the clinical development. These models differ from descriptive PK-PD models in that they quantitatively characterize specific processes in the causal chain be- tween drug administration and effect. This includes target site distribution, binding and activation, phar- macodynamic interactions, transduction and homeostatic feedback mechanisms. Compared to descriptive models mechanism-based PK-PD models that utilize receptor theory concepts for characterization of target binding and target activation processes have improved properties for extrapolation and prediction. In this respect, receptor theory constitutes the basis for 1) prediction of in vivo drug concentration-effect relation- ships and 2) characterization of target association-dissociation kinetics as determinants of hysteresis in the time course of the drug effect. This approach intrinsically distinguishes drug- and system specific parameters explicitly, allowing accurate extrapolation from in vitro to in vivo and across species. This review provides an overview of recent developments in incorporating receptor theory in PK-PD modeling with a specific focus on the identifiability of these models. Keywords: receptor theory; mechanism-based Pharmacokinetic-Pharmacodynamic modeling; kinetics of drug action; Operational Model of Agonism, target site distribution bringing forward early (discovery and preclinical) insights Introduction in drug efficacy and safety into the clinical development Pharmacokinetic-Pharmacodynamic modeling (PK-PD) stage.12) Mechanism-based PK-PD models differ from em- and simulation has been recognized as a key factor to im- pirical PK-PD models in that they quantitatively charac- prove the efficiency of the drug-development process, terize specific processes in the causal chain between drug which is facing high attrition rates. Over the years, the administration and effect.6) However, for their part, useofPK-PDmodelingtobetterunderstanddrugeffica- mechanism-based PK-PD models differ from full cy and safety, thereby improving the quality of decision mechanistic or systems biology models. In mechanism- making in drug-development, has been advocated by based PK-PD modeling one follows a data driven, top- pharmaceutical companies,1–5) academia6,7) and regulato- down approach starting at a parsimonious descriptive lev- ry agencies.7–9) When these insights are obtained in early el and subsequently add more complexity to better un- development they can be used in a translational approach derstand the system. Hence, the parameters in these to better predict efficacy and safety in the later stages of models are composites of the actual (patho)-physiological clinical development.6,10) This will reduce the attrition and pharmacological processes. On the other hand, sys- risk during clinical development due to lack of efficacy tems biology models are inherently complete and fully or safety.11) In translational drug-research, mechanism- mechanistic and follows a bottom-up approach, starting based PK-PD modeling has evolved as an essential tool for from the level of molecular pathways.13) Using the ter- Received; October 31, 2008, Accepted; December 18, 2008 *To whom correspondence should be addressed: Bart PLOEGER, LAP&P Consultants BV, Archimedesweg 31, 2333 CM Leiden, The Netherlands. Tel. ＋31715243005, fax. ＋31715243001, E-mail: b.ploeger＠lapp.nl 3 4 Bart A. PLOEGER, et al. Fig. 1. Processes in the causal chain between drug administration and the change in response over time, including the phar- macokinetics of a drug (process A), target site distribution and receptor (target) binding kinetics (process B), receptor activation (process C) and transduction (process D) These processes are characterized by receptor theory models incorporated in mechanism-based PK-PD models. These models explicitly distinguish drug and system specific properties, which are shown in the solid white and shaded area's respectively. Cl, clearance; V, volume of distribution; Ka, absorption rate constant; Ke0, biophase distribution constant; kon, association rate constant; koff, dissociation rate constant; KA, receptor affinity; e, intrinsic efficacy; KAR, receptor occupancy resulting in 50% stimulus; Em, maximum effect; nE slope of stimulus-response relationship; KE, stimulus resulting in 50% effect. minology of Weiss et al., who distinguished parsimonious chain include target site distribution, target binding and and heuristic models at the extremes of the modeling activation, pharmacodynamic interactions, transduction philosophy spectrum,14) empirical PK-PD models are the and homeostatic feedback mechanisms. Consequently, parsimonious and systems biology models the heuristic changes in these processes due to disease progress can be models in the PK-PD modeling spectrum. The complexity considered.15,16) These mechanism-based PK-PD models of the empirical models is limited by the identifiability of utilize receptor theory concepts for characterization of the parameters, whereas systems biology models are not target binding and target activation processes.6) In this limited in terms of complexity. Mechanism-based PK-PD respect, receptor theory constitutes the basis for 1) modeling can be found somewhere in the middle of this prediction of in vivo drug concentration-effect relation- spectrum, i.e. trying to be as mechanistic as possible ships and 2) characterization of target association-dissoci- while still considering the identifiability of the ation kinetics as determinants of hysteresis in the time parameters. course of the drug effect. As this approach intrinsically As illustrated in Figure 1 the processes on the causal distinguishes drug- and biological-system specific Receptor Theory in Mechanism-Based PK-PD Modeling 5 parameters it allows accurate extrapolation from in vitro response relationships under equilibrium conditions is to in vivo and from one species to another, which are the well established, its intrinsically descriptive nature limits key processes in translational drug research. its use for extrapolation. For instance, the Hill equation The principles of receptor theory date back to the for the concentration-effect relationship cannot be readi- pivotal work of Clark and Gaddum in the 1930s, based ly used to predict this relationship in another tissue with on earlier work of Hill,17) providing the basics of Black a different receptor density or another stimulus-response and Leff's operational model of agonism18) and it's princi- relationship. This would require a mechanism-based ples and applications have been extensively reviewed by model that separates drug from system-specific others.6,19) However, recognition of mechanism-based parameters. Classical receptor theory can be applied for PK-PD modeling as a valuable tool in translational drug making this separation, since it describes drug action by research has led to new developments in incorporating 2 independent parts, which relate to drug-specific (i.e. receptor theory in this emerging science. In this review the agonist-dependent part) and system specific proper- we will discuss these developments with a specific focus ties (i.e. the tissue-dependent part). Hence, receptor the- on how to predict in vivo drug concentration-effect ory constitutes a scientific basis for the prediction of in relationships under equilibrium (steady state) conditions. vivo concentration-effect relationships.6) Moreover, we will discuss the application of receptor The system specific part is determined by the receptor theory to describe the kinetics of drug action (i.e. drug ef- concentration, which determines the receptor binding fects under non equilibrium conditions) by characteriz- capacity and the nature of the stimulus response relation- ing target site distribution and receptor association and ship or transducer function (process D in Fig. 1). Recep- dissociation. However, this review primarily focuses on tor binding and activation determine the drug-specific mechanism-based PK-PD modeling and does not include component (process C in Fig. 1). In all approaches to in- a discussion on alternative approaches in the PK-PD corporate receptor theory in PK-PD modeling the recep- modeling spectrum, such as systems biology modeling. tor or target binding component is described with a For a discussion on systems biology modeling in drug de- hyperbolic function, typically the Hill-Langmuir equation velopment we refer to the review of Butcher et al.13) (i.e. the Hill equation with a Hill factor fixed to 1). On the other hand, the stimulus-response relationship has Equilibrium in vivo been incorporated in different ways, which
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