Chapter 10: Transporter Drug–Drug Interactions: A Pharmaceutical Industry Perspective
Published:16 Aug 2016
S. Simon, M. Ullah, R. V. Waterschoot, D. Schwab, S. Grange, C. A. Lee, and C. Funk, in Drug Transporters: Volume 1: Role and Importance in ADME and Drug Development, ed. G. Nicholls, K. Youdim, G. Nicholls, and K. Youdim, The Royal Society of Chemistry, 2016, vol. 1, ch. 10, pp. 361-417.
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Over the last few decades, active drug transporters have gained increasing attention in basic and applied research, since they can substantially modulate drug absorption, distribution, metabolism and excretion (ADME) routes, interact with co-medications and endogenous products, and thereby strongly impact drug efficacy and safety profiles. Therefore, these interactions between substrates and inhibitors need to be assessed during drug development and are part of every new entity's pharmacokinetic (PK) and safety package. This chapter provides a general overview of the most important drug–drug interaction (DDI) aspects from a pharmaceutical industry perspective. Clinically relevant DDIs at the various barrier tissues are described via a comprehensive DDI table, listing substrate–inhibitor pairs with the respective PK/pharmacodynamic (PD) effects and their implicated therapeutic consequences. Transporter DDI assessment during the early and late drug development stages is discussed, followed by insights into a clinical strategy paradigm to address this issue in humans. Both sections emphasize the importance of adjusting a transporter DDI strategy individually to the characteristics of the compound and the project, and the difficulty of interpreting the obtained data correctly. Two prominent transporter DDI examples are discussed as case studies: digoxin and the cholesterol-reducing statins. The chapter concludes by outlining the current gaps and future challenges in this emerging field.