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Drug development for the central nervous system (CNS) is a complex endeavour with low success rates, as the structural complexity of the brain and specifically the blood-brain barrier (BBB) poses tremendous challenges. Several  in vitro  brain systems have been evaluated, but the ultimate use of these data in terms of translation to human brain concentration profiles remains to be fully developed. Thus, linking up  in vitro-to-in vivo  extrapolation (IVIVE) strategies to physiologically based pharmacokinetic (PBPK) models of brain is a useful effort that allows better prediction of drug concentrations in CNS components. Such models may overcome some known aspects of inter-species differences in CNS drug disposition. Required physiological (i.e. systems) parameters in the model are derived from quantitative values in each organ. However, due to the inability to directly measure brain concentrations in humans, compound-specific (drug) parameters are often obtained from  in silico  or  in vitro  studies. Such data are translated through IVIVE which could be also applied to preclinical  in vivo  observations. In such exercises, the limitations of the assays and inter-species differences should be adequately understood in order to verify these predictions with the observed concentration data. This report summarizes the state of IVIVE-PBPK-linked models and discusses shortcomings and areas of further research for better prediction of CNS drug disposition.

In Vitro to In Vivo Extrapolation Linked to Physiologically Based Pharmacokinetic Models for Assessing the Brain Drug Disposition