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Drug–Drug Interaction Studies: Regulatory Guidance and An Industry Perspective

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Abstract

Recently, the US Food and Drug Administration and European Medicines Agency have issued new guidance for industry on drug interaction studies, which outline comprehensive recommendations on a broad range of in vitro and in vivo studies to evaluate drug–drug interaction (DDI) potential. This paper aims to provide an overview of these new recommendations and an in-depth scientifically based perspective on issues surrounding some of the recommended approaches in emerging areas, particularly, transporters and complex DDIs. We present a number of theoretical considerations and several case examples to demonstrate complexities in applying (1) the proposed transporter decision trees and associated criteria for studying a broad spectrum of transporters to derive actionable information and (2) the recommended model-based approaches at an early stage of drug development to prospectively predict DDIs involving time-dependent inhibition and mixed inhibition/induction of drug metabolizing enzymes. We hope to convey the need for conducting DDI studies on a case-by-case basis using a holistic scientifically based interrogative approach and to communicate the need for additional research to fill in knowledge gaps in these areas where the science is rapidly evolving to better ensure the safety and efficacy of new therapeutic agents.

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ACKNOWLEDGMENTS

We would like to thank Drs. Ying-Hong Wang, Jairam Palamanda, Prajakti Kothare, Raymond Evers, and David Cutler for their help and valuable inputs, and Drs. Jane Croft Harrelson, Nancy Agrawal, Richard Morrison, and James Yergey for their critical review of the manuscript.

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  1. Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Sharp and Dohme Corp., WP 75A-203, West Point, Pennsylvania, 19486, USA

    Thomayant Prueksaritanont, Christopher Gibson, Donghui Cui, Ka Lai Yee, Jeanine Ballard, Tamara Cabalu & Jerome Hochman

  2. Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Sharp and Dohme Corp., Rahway, New Jersey, 07065, USA

    Xiaoyan Chu

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  1. Thomayant Prueksaritanont
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Correspondence to Thomayant Prueksaritanont.

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Prueksaritanont, T., Chu, X., Gibson, C. et al. Drug–Drug Interaction Studies: Regulatory Guidance and An Industry Perspective. AAPS J 15, 629–645 (2013). https://doi.org/10.1208/s12248-013-9470-x

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  • DOI: https://doi.org/10.1208/s12248-013-9470-x

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