Navigating Drug–Drug Interactions in Clinical Drug Development: A Tutorial

Abstract

This tutorial provides essential guidelines and insights, in addition to regulatory guidance, for the evaluation of drug–drug interactions (DDIs), with a focus on the tools and timing of assessment critical for effective management of inclusion/exclusion criteria during drug development and accurate labeling of investigational drugs. It aims to equip researchers with the knowledge and methodologies required to identify and evaluate DDIs, addressing both victim (investigational drugs that are affected by concomitant medications) and perpetrator (investigational drugs that cause changes in the PK of concomitant medications) interactions. The tutorial explores the mechanistic basis of DDIs, explaining how such interactions can alter drug absorption, distribution, metabolism, and excretion, potentially influencing the benefit-to-risk profile. The tutorial further highlights the tools and methodologies employed in assessing drug–drug interactions (DDIs) across various stages of development. It outlines the importance of in vitro studies for early-stage screening of enzyme- and transporter-mediated interactions to identify potential perpetrators, followed by in vivo studies to confirm these findings. Additionally, it explores the application of computational modeling approaches, such as physiologically based pharmacokinetic (PBPK) modeling and population pharmacokinetic (popPK) approaches, where feasible, to predict both victim and perpetrator interactions prior to or in addition to clinical trials. The aim of this tutorial is to serve as a comprehensive resource for DDI considerations when developing a new molecular entity, supporting researchers during clinical drug development.