The Conduct of In Vitro and In Vivo Drug‐Drug Interaction Studies: A PhRMA Perspective

TLDR

Regulatory guidance currently lacks specific designs for drug‑drug interaction studies, prompting a push to harmonize approaches, standardize CYP probe substrates, and address transporter‑mediated interactions. The paper aims to establish minimal best practices for in vitro and in vivo pharmacokinetic drug‑drug interaction studies and outline the data package regulators expect in registration dossiers. The authors propose a minimal best‑practice framework for conducting these studies and specify the data package required for regulatory submissions. Prepared by PhRMA’s Drug Metabolism and Clinical Pharmacology Technical Working Groups, the paper reflects the current industry position.

Abstract

Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (CYP) probe substrates, inhibitors, and inducers and for the development of classification systems to improve the communication of risk to health care providers and patients. While existing guidances cover mainly CYP-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently and should also be addressed. This paper was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.