Utilizing PBPK Modeling to Evaluate the Potential of a Significant Drug-Drug Interaction Between Clopidogrel and Dasabuvir: A Scientific Perspective

V Arya; P Zhao; K S Reynolds; P Mishra; I R Younis

doi:10.1002/cpt.699

Utilizing PBPK Modeling to Evaluate the Potential of a Significant Drug-Drug Interaction Between Clopidogrel and Dasabuvir: A Scientific Perspective

Clin Pharmacol Ther. 2017 Oct;102(4):578-580. doi: 10.1002/cpt.699. Epub 2017 Apr 26.

Authors

V Arya¹, P Zhao², K S Reynolds¹, P Mishra³, I R Younis¹

Affiliations

¹ Division of Clinical Pharmacology IV, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.
² Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.
³ Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.

PMID: 28444890
DOI: 10.1002/cpt.699

Abstract

Dasabuvir, a component of VIEKIRA PAK, is a substrate of CYP2C8 enzymes. Prescribing information for VIEKIRA PAK contraindicates gemfibrozil, a strong CYP2C8 inhibitor, because coadministration significantly increases dasabuvir exposures, which may increase the risk of QT prolongation. Clopidogrel may increase dasabuvir exposures primarily due to CYP2C8 inhibition by clopidogrel-acyl-β-D-glucuronide. This commentary outlines the US Food and Drug Administration (FDA) interdisciplinary review team's scientific perspective to address the potential for a significant drug-drug interaction (DDI) between clopidogrel and VIEKIRA PAK.

Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

MeSH terms

2-Naphthylamine
Antiviral Agents / pharmacokinetics
Clopidogrel
Cytochrome P-450 CYP2C8 / drug effects
Cytochrome P-450 CYP2C8 / metabolism*
Drug Combinations
Drug Interactions
Glucuronides
Humans
Macrocyclic Compounds / administration & dosage
Macrocyclic Compounds / pharmacokinetics
Models, Biological*
Ritonavir / administration & dosage
Ritonavir / pharmacokinetics
Sulfonamides / administration & dosage
Sulfonamides / pharmacokinetics*
Ticlopidine / analogs & derivatives*
Ticlopidine / metabolism
Ticlopidine / pharmacology
Uracil / administration & dosage
Uracil / analogs & derivatives*
Uracil / pharmacokinetics

Substances

Antiviral Agents
Drug Combinations
Glucuronides
Macrocyclic Compounds
Sulfonamides
Viekira Pak
Uracil
Clopidogrel
2-Naphthylamine
dasabuvir
Cytochrome P-450 CYP2C8
Ritonavir
Ticlopidine