Recent Advances in Development and Application of Physiologically-Based Pharmacokinetic (PBPK) Models: a Transition from Academic Curiosity to Regulatory Acceptance

Abstract

There is a renewed surge of interest in applications of physiologically-based pharmacokinetic (PBPK) models by the pharmaceutical industry and regulatory agencies. Developing PBPK models within a systems pharmacology context allows separation of the parameters pertaining to the animal or human body (the system) from that of the drug and the study design which is essential to develop generic drug-independent models used to extrapolate PK/PD properties in various healthy and patient populations. This has expanded the classical paradigm to a 'predict-learn-confirm-apply' concept. Recently, a number of drug labels are informed by simulation results generated using PBPK models. These cases show that either the simulations are used in lieu of conducting clinical studies or have informed the drug label that otherwise would have been silent in some specific situations. It will not be surprising to see applications of these models in implementing precision dosing at the point of care in the near future.

Keywords: In vitro in vivo extrapolation; Modelling and simulation; Physiologically-based pharmacokinetics; Precision medicine; Regulatory science; Systems pharmacology.

Fig. 1

A schematic of systems pharmacology paradigm where the systems, drug and trial design data are mechanistically combined and integrated within PBPK models to simulate and predict the drug PK/PD in virtual populations. The Systems and Data are part of the trial setting thence included in the Trial Design box

Fig. 2

The distribution of area of applications of 136 regulatory submissions to FDA (until Oct 2014) where PBPK modelling has been applied, updated by Grillo [10] after [14]