Implementation of variability in a physiologically-based pharmacokinetic approach for simulating the first-in-animal study.

PDF of poster

Objectives: The objective of this study was to evaluate the influence of different sources of variability in a basic, generic physiology-based pharmacokinetic (PB-PK) model used for simulating the first-in-animal study.

Methods: The basic model (1), partially modified from the one developed by Poulin & Theil (2), comprised a system of differential equations describing 13 tissue compartments. The model was based on physiological parameters, such as tissue volumes, weights, composition and blood flows, and compound-specific parameters (logP, pKa, hepatocyte intrinsic clearance, fraction unbound in plasma) obtained in vitro or estimated in silico. The variability of these input parameters were derived from the literature (3) and from the experimental data, respectively. Stochastic simulations of plasma concentration-time curves were generated using Matlab.

Results: Normal or log-normal distributions were implemented for describing the variability of parameters. Preliminary data suggest that the variability of physiological data is less important than the variability of the compound-specific input parameters. The basic model was also modified to consider alternative administration routes, such as inhalation. The approach provided results in good agreement with those reported in the literature (4).

Conclusions: The implementation of stochastic simulations into the basic PBPK model allowed to simulate not only the average pharmacokinetic profile, but also the dispersion of the data, considering the different sources of variability in the model parameters.

References:
(1) Germani M, Crivori P, Rocchetti M, Burton PS, Wilson AG, Smith ME, Poggesi I. Evaluation of a physiologically-based pharmacokinetic approach for simulating the first-time-in-animal study. Basic Clin Pharmacol Toxicol. 96:254-6, 2005. 
(2) Poulin P. & F. P. Theil: Prediction of pharmacokinetics prior to in vivo studies. II. Generic physiologically based pharmacokinetic models of drug disposition. J Pharm Sci, 91, 1358-1370, 2002.
(3) Price PS, Conolly RB, Chaisson CF, Gross EA, Young JS, Mathis ET, Tedder DR. Modeling interindividual variation in physiological factors used in PBPK models of humans. Critical Reviews in Toxicology. 33:469-503, 2003.
(4) Bonate PL, Swann A, Silverman PB. Preliminary physiologically based pharmacokinetic model for cocaine in the rat: model development and scale-up to humans. J Pharm Sci 85, 881 1996.