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

Masoud Jamei

doi:10.1007/s40495-016-0059-9

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.

Highlights

Physiologically-based pharmacokinetic (PBPK) models map drug movements in the body to a physiologically realistic compartmental structure using sets of differential equations
Since the number of regulatory submissions using PBPK models is rapidly increasing, the regulators have started discussing various aspects of the best practice in PBPK modelling with researchers in the field
Zhao and co-workers have described the best practice in the use of PBPK modelling and simulation for a PBPK regulatory submission to address clinical pharmacology questions and summarised what contents should be included [41]

Summary

Introduction

Physiologically-based pharmacokinetic (PBPK) models map drug movements in the body to a physiologically realistic compartmental structure using sets of differential equations. In a systems pharmacology context, the PBPK model parameters should be divided into three categories, namely, the system or species (e.g. age, weight, height, genetic make-up, etc., of human or animal subjects), the drug (e.g. physicochemical characteristics determining permeability through membranes, partitioning to tissues, binding to plasma proteins, or affinities towards certain enzymes and transporter proteins) and the study design (e.g. dose, route and frequency of administration, the effect of concomitant drugs and food) [16].

Results

Conclusion