Sabrina Salhi and Roberto Gomeni
GlaxoSmithKline - Clinical Pharmacokinetic & Modelling and Simulation, Verona, Italy
Objectives:A Physiologically Based Whole Body Pharmacokinetic/ Pharmacodynamic (WBPBPK/PD) is today recognised as knowledge- based mechanistic modelling approach to integrate the current information on a compound across species. This approach constitutes a rational basis to scale-up in-vitro and preclinical data to human, to explain differences among compounds based on physicochemical and structural properties and to predict likely PK/PD response in humans. The aim of this study was to develop and validate a population WBPBPK/PD model for CNS compounds considering the impact on predictions of uncertainty and variability in physiological (blood flow and tissue volume) and drug specific (CL, fu,..) parameters on a target pharmacodynamic response (the brain receptor occupancy, considered as a surrogate marker of pharmacological drug activity) .
Methods:A WBPBPK/PD model was developed using animal and human blood flows and tissue volumes derived from the literature [1]. The whole body model consisted of nine tissue compartments and two blood compartments namely brain, lung, heart, gut, liver, kidney, muscle, skin, adipose, arterial and venous blood. Saturable liver metabolism was considered as the main elimination process. The impact on model PK/PD predictions of parameter uncertainty and inter-individual variability was assessed using Monte Carlo simulations. Different levels of inter-individual variability were explored assuming different statistical distributions of parameters using Berkeley Madonna software (version 8.0.1, University of California at Berkeley). For each evaluation, 1000 simulations were done: the results are presented as an average response with 95% prediction confidence intervals. The comparison of simulated and observed data was used to assess the consistency of the model predictions (plasma and brain drug concentrations in animal and plasma concentrations and brain receptor occupancy estimated in a PET experiment for human). Distribution, metabolism, absorption and pharmacodynamic data were the drug specific input parameters considered in the model. The tissue composition model was used to estimate the tissue: plasma partition coefficients under in vivo conditions [2]. Prior estimates of variability on model parameters were derived from published studies [3]. A PK/PD model based on a direct link between plasma/ brain and pharmacological effect was developed using a sigmoid- Emax model for animal: this was used to predict the brain receptor occupancy in man.
Results and conclusion:The proposed model accurately predicted the animal PK/PD response while the scaled model properly described the PK/PD observations in human. Furthermore, the incorporation of variability and uncertainty into PK/PD model parameters allowed the derivation of an accurate estimate of the inter-individual variability in human plasma concentration and receptor occupancy. The proposed WBPBPK/PD modeling strategy can be applied in early drug discovery, prior to in vivo study using in silico and in vitro data to predict plasma and tissue PK of drug candidates. This approach could also support a better mechanistic understanding of PK properties by developing mechanism-based PK/PD relationships from predicted tissue kinetic data. This would facilitate more rational decision making during clinical candidate selection, and the scaling up of PK and PK/PD relationships across species, routes of administration and dose levels.
References:
[1]Bernareggi, A. & Rowland, M. (1991) Pysiologic modeling of cyclosporin kinetics in rat and man. J. Pharmacokinet. Biopharm, 19, 21-50.
[2] Poulin, P. (1999) A priori prediction of Kp to facilitate the use of PBPK models. J. Pharm. Sci., 89, 16-35.
[3]Thomas, R. (1996). Variability in biological exposure indices using PBPK modeling and Monte Carlo simulation. Am. Ind. Hyg. Assoc. J. , 57, 25-32.
Reference: PAGE 12 (2003) Abstr 443 [www.page-meeting.org/?abstract=443]
Poster: poster