How Informative Are Drug‐Drug Interactions of Gene‐Drug Interactions?

Lagishetty, Chakradhar V.; Deng, Jiexin; Lesko, Lawrence J.; Rogers, Hobart; Pacanowski, Michael; Schmidt, Stephan

doi:10.1002/jcph.743

How Informative Are Drug‐Drug Interactions of Gene‐Drug Interactions?

Journal Article · Tue Apr 26 00:00:00 EDT 2016 · Journal of Clinical Pharmacology

DOI:https://doi.org/10.1002/jcph.743· OSTI ID:1400958

Lagishetty, Chakradhar V. ^[1]; Deng, Jiexin ^[1]; Lesko, Lawrence J. ^[1]; Rogers, Hobart ^[2]; Pacanowski, Michael ^[2]; Schmidt, Stephan ^[1]

Center for Pharmacometrics and Systems Pharmacology College of Pharmacy University of Florida at Lake Nona Orlando FL, USA
FDA Genomics and Targeted Therapy Group Office of Clinical Pharmacology Office of Translational Sciences CDER, US FDA Silver Spring MD, USA

Abstract

FDA recommendations to manage polymorphic CYP‐mediated drug‐drug interactions (DDIs) and gene‐drug interactions (GDIs) are typically similar. However, DDIs may not always reliably predict GDIs because the victim drug may have multiple metabolic pathways and the perpetrator drug may affect multiple enzymes or transporters. Consequently, it is of great interest to both the pharmaceutical industry and regulatory agencies to determine if DDI studies can be leveraged to inform GDIs or vice versa for dose adjustment and labeling. The objective of this study was to investigate under what circumstances DDIs can be used to predict GDIs for prototypical CYP2C9, CYP2C19, and CYP2D6 substrates. We investigated model substrates for CYP2D6 (metoprolol, dextromethorphan, atomoxetine, and vortioxetine), CYP2C9 (warfarin, flurbiprofen, and celecoxib), and CYP2C19 (omeprazole and clopidogrel). Data on drug exposure for poor metabolizers (GDI) and for DDIs mediated by strong/moderate inhibitors in extensive metabolizers were collected. The impact of DDIs and GDIs on drug exposure was compared using: (1) a descriptive and (2) a physiologically based pharmacokinetic convergence analysis. Results from both approaches indicate that information on DDIs can be used to reliably predict GDIs for CYP2D6 substrates. The situation is more complex for CYP2C9 and CYP2C19 substrates because dose of the inhibitor (CYP2C9) and potency of the inhibitor (CYP2C19) impact the extent to which perpetrator drugs phenotypically convert extensive metabolizers to poor(er) metabolizers.

View Accepted Manuscript (Publisher)

Sponsoring Organization:: USDOE

OSTI ID:: 1400958

Journal Information:: Journal of Clinical Pharmacology, Journal Name: Journal of Clinical Pharmacology Journal Issue: 10 Vol. 56; ISSN 0091-2700

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: United States

Language:: English

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