Utility of physiologically based pharmacokinetic modeling in predicting and characterizing clinical drug interactions

Abstract

Physiologically based pharmacokinetic (PBPK) modeling is a mechanistic dynamic modeling approach that can be used to predict or retrospectively describe changes in drug exposure due to drug-drug interactions (DDIs). With advancements in commercially available PBPK software, PBPK DDI modeling has become a mainstream approach from early drug discovery through to late-stage drug development and is often used to support regulatory packages for new drug applications. This Minireview will briefly describe the approaches to predicting DDI using PBPK and static modeling approaches, the basic model structures and features inherent to PBPK DDI models, and key examples where PBPK DDI models have been used to describe complex DDI mechanisms. Future directions aimed at using PBPK models to characterize transporter-mediated DDI, predict DDI in special populations, and assess the DDI potential of protein therapeutics will be discussed. A summary of the 209 PBPK DDI examples published to date in 2023 will be provided. Overall, current data and trends suggest a continued role for PBPK models in the characterization and prediction of DDI for therapeutic molecules. SIGNIFICANCE STATEMENT: Physiologically based pharmacokinetic (PBPK) models have been a key tool in the characterization of various pharmacokinetic phenomena, including drug-drug interactions. This Minireview will highlight recent advancements and publications around physiologically based pharmacokinetic drug-drug interaction modeling, an important area of drug discovery and development research in light of the increasing prevalence of polypharmacology in clinical settings.

Keywords: Cytochrome P450; Drug transporters; Drug-drug interaction (DDI); Physiologically-based pharmacokinetic (PBPK) model.