Interactions of the hepatitis C virus protease inhibitor faldaprevir with cytochrome P450 enzymes: in vitro and in vivo correlation

J Clin Pharmacol. 2015 Apr;55(4):467-77. doi: 10.1002/jcph.436. Epub 2015 Jan 14.


The potential inhibition of the major human cytochrome P450 (CYP) enzymes by faldaprevir was evaluated both in vitro and in clinical studies (healthy volunteers and hepatitis C virus [HCV] genotype 1-infected patients). In vitro studies indicated that faldaprevir inhibited CYP2B6, CYP2C9, and CYP3A, and was a weak-to-moderate inactivator of CYP3A4. Faldaprevir 240 mg twice daily in healthy volunteers demonstrated moderate inhibition of hepatic and intestinal CYP3A (oral midazolam: 2.96-fold increase in AUC(0-24 h)), weak inhibition of hepatic CYP3A (intravenous midazolam: 1.56-fold increase in AUC(0-24 h)), weak inhibition of CYP2C9 ([S]-warfarin: 1.29-fold increase in AUC(0-120 h)), and had no relevant effects on CYP1A2, CYP2B6, or CYP2D6. Faldaprevir 120 mg once daily in HCV-infected patients demonstrated weak inhibition of hepatic and intestinal CYP3A (oral midazolam: 1.52-fold increase in AUC(0-∞)), and had no relevant effects on CYP2C9 or CYP1A2. In vitro drug-drug interaction predictions based on inhibitor concentration ([I])/inhibition constant (Ki) ratios tended to overestimate clinical effects and a net-effect model provided a more accurate approach. These studies suggest that faldaprevir shows a dose-dependent inhibition of CYP3A and CYP2C9, and does not induce CYP isoforms.

Keywords: clinical research (CRE); clinical trials (CTR); drug interactions; infectious diseases (INF); pharmacokinetics and drug metabolism.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Cytochrome P-450 Enzyme Inhibitors / pharmacology*
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dose-Response Relationship, Drug
  • Female
  • Healthy Volunteers
  • Hepatitis C / metabolism
  • Humans
  • In Vitro Techniques
  • Isoenzymes / metabolism
  • Male
  • Microsomes, Liver / drug effects
  • Midazolam / pharmacokinetics
  • Middle Aged
  • Oligopeptides / pharmacology*
  • Protease Inhibitors / pharmacology*
  • Thiazoles / pharmacology*
  • Warfarin / pharmacokinetics
  • Young Adult


  • Cytochrome P-450 Enzyme Inhibitors
  • Isoenzymes
  • N-((cyclopentyloxy)carbonyl)-3-methylvalyl-4-((8-bromo-7-methoxy-2-(2-((2-methylpropanoyl)amino)-1,3-thiazol-4-yl)quinolin-4-yl)oxy)-N-(1-carboxy-2-ethenylcyclopropyl)prolinamide
  • Oligopeptides
  • Protease Inhibitors
  • Thiazoles
  • Warfarin
  • Cytochrome P-450 Enzyme System
  • Midazolam