Diazepam Pharamacokinetics from Preclinical to Phase I Using a Bayesian Population Physiologically Based Pharmacokinetic Model with Informative Prior Distributions in Winbugs

Modelling is an important applied tool in drug discovery and development for the prediction and interpretation of drug pharmacokinetics. Preclinical information is used to decide whether a compound will be taken forwards and its pharmacokinetics investigated in human. After proceeding to human little to no use is made of these often very rich data. We suggest a method where the preclinical data are integrated into a whole body physiologically based pharmacokinetic (WBPBPK) model and this model is then used for estimating population PK parameters in human. This approach offers a continuous flow of information from preclinical to clinical studies without the need for different models or model reduction. Additionally, predictions are based upon single parameter values, but making realistic predictions involves incorporating the various sources of variability and uncertainty. Currently, WBPBPK modelling is undertaken as a two-stage process: (i) estimation (optimisation) of drug-dependent parameters by either least squares regression or maximum likelihood and (ii) accounting for the existing parameter variability and uncertainty by stochastic simulation. To address these issues a general Bayesian approach using WinBUGS for estimation of drug-dependent parameters in WBPBPK models is described. Initially applied to data in rat, this approach is further adopted for extrapolation to human, which allows retention of some parameters and updating others with the available human data. While the issues surrounding the incorporation of uncertainty and variability within prediction have been explored within WBPBPK modeling methodology they have equal application to other areas of pharmacokinetics, as well as to pharmacodynamics.