Predicting transporter mediated drug-drug interactions via static and dynamic physiologically based pharmacokinetic modeling: A comprehensive insight on where we are now and the way forward.

Abstract

The greater utilization and acceptance of physiologically-based pharmacokinetic (PBPK) modeling to evaluate the potential metabolic drug-drug interactions is evident by the plethora of literature, guidance's, and regulatory dossiers available in the literature. In contrast, it is not widely used to predict transporter-mediated DDI (tDDI). This is attributed to the unavailability of accurate transporter tissue expression levels, the absence of accurate in vitro to in vivo extrapolations (IVIVE), enzyme-transporter interplay, and a lack of specific probe substrates. Additionally, poor understanding of the inhibition/induction mechanisms coupled with the inability to determine unbound concentrations at the interaction site made tDDI assessment challenging. Despite these challenges, continuous improvements in IVIVE approaches enabled accurate tDDI predictions. Furthermore, the necessity of extrapolating tDDI's to special (pediatrics, pregnant, geriatrics) and diseased (renal, hepatic impaired) populations is gaining impetus and is encouraged by regulatory authorities. This review aims to visit the current state-of-the-art and summarizes contemporary knowledge on tDDI predictions. The current understanding and ability of static and dynamic PBPK models to predict tDDI are portrayed in detail. Peer-reviewed transporter abundance data in special and diseased populations from recent publications were compiled, enabling direct input into modeling tools for accurate tDDI predictions. A compilation of regulatory guidance's for tDDI's assessment and success stories from regulatory submissions are presented. Future perspectives and challenges of predicting tDDI in terms of in vitro system considerations, endogenous biomarkers, the use of empirical scaling factors, enzyme-transporter interplay, and acceptance criteria for model validation to meet the regulatory expectations were discussed.