Role of PBPK modeling in drug discovery: opportunities and limitations

During drug discovery, considerable resources are required to assess the pharmacokinetic properties of potential drug candidates in vivo in animals and there is interest in optimizing the use of such testing by applying simulation. Physiologically based pharmacokinetic (PBPK) models take in vitro and in silico data inputs to predict concentration versus time profiles before any in vivo experiment is performed. If sufficiently reliable, such simulations could decrease the turnaround time for delivery of information to medicinal chemists during the optimization phase and could also be used to prioritize compounds for the more costly in vivo testing. The mechanistic framework provided by a PBPK model can integrate most of the available predictive data on a compound and provide mechanistic insights into compound properties. Such integrative capabilities and mechanistic insights are not provided by the more commonly used non compartmental or compartmental analysis. However, there are still important processes missing in the models, such as active transport processes, which are the subject of intensive investigation. Thus, mechanistic models integrating active transport processes were developed and are currently being validated. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)