Physiologically Based Pharmacokinetics Is Impacting Drug Development and Regulatory Decision Making

It is no coincidence that the reports of two meetings, one organized by the US Food and Drug Administration (FDA), in March 2014, and the other by the UK Medicines and Healthcare Products Regulatory (MHRA), in collaboration with ABPI (the Association of British Pharmaceutical Industry), in June 2014, have been published in tandem in CPT-PSP.12 Both reports deal with the same topic, namely, the impact of physiologically based pharmacokinetics (PBPK) in clinical drug development and the best practices for such applications. This reflects the transition of PBPK from academic curiosity to industrial norm, manifested by the regulatory agencies encouraging its use and receiving an increasing number of submissions containing PBPK models. The goal of both meetings was to help determine the need and facilitate the development of regulatory guidances on this subject within the conceptual framework of model informed drug development and regulatory decision-making. A further reflection of this intent is the publication by the European Medicines Agency of a Concept Paper on PBPK.3 One is reminded of a similar train of events surrounding the introduction of population PK/PD and nonlinear mixed effects modeling in the early-late 1990s, again with encouragement and receptivity of regulatory agencies leading to FDA guidance on the topic.4 Indeed, the intention of PBPK modeling and simulation is to complement other approaches, such as compartmental modeling, or, in some cases, replace them with a more mechanistic approach. PBPK models represent an important class of models that characterize absorption, distribution, metabolism, excretion (ADME) processes and their underlying biological and physiological drivers. An increased understanding of these drivers and their unique interactions with drug substance and formulation factors provides critical insights into how drugs will behave in healthy volunteers and patients with disease.