A randomised study of the effect of danoprevir/ritonavir or ritonavir on substrates of cytochrome P450 (CYP) 3A and 2C9 in chronic hepatitis C patients using a drug cocktail

Eur J Clin Pharmacol. 2013 Nov;69(11):1939-49. doi: 10.1007/s00228-013-1556-y. Epub 2013 Jul 20.

Abstract

Purpose: The aim of this study was to evaluate the effects of danoprevir in combination with low-dose ritonavir (danoprevir/r) and placebo plus low-dose ritonavir on the pharmacokinetics of probe drugs for cytochrome P450 (CYP) 3A and CYP2C9, in patients with chronic hepatitis C.

Methods: A total of 54 patients infected with hepatitis C virus genotype 1 received an oral drug cocktail (2 mg midazolam, 10 mg warfarin and 10 mg vitamin K) before and after 14 days of dosing with either danoprevir/r or placebo plus low-dose ritonavir (placebo/r). Serial pharmacokinetic samples were collected up to 24 (midazolam) and 72 (S-warfarin) h post-dose. Plasma concentrations of midazolam, α-hydroxymidazolam and S-warfarin were measured using validated assays. Pharmacokinetic parameters were estimated using non-compartmental analysis, and geometric mean ratios (GMRs) and 90 % confidence intervals (CIs) for the differences between baseline and post-dosing values were calculated.

Results: Danoprevir/r and placebo/r significantly increased midazolam area under the time-concentration curve (AUC0-∞) and reduced the midazolam metabolic ratio while S-warfarin AUC0-∞ was modestly decreased. When danoprevir data were pooled across doses, the midazolam GMR (90 % CI) AUC0-∞ was 9.41 (8.11, 10.9) and 11.14 (9.42, 13.2) following danoprevir/r and placebo/r dosing, respectively, and the S-warfarin GMR (90 % CI) AUC0-∞ was 0.72 (0.68, 0.76) and 0.76 (0.69, 0.85), respectively. The effects of danoprevir/r and placebo/r appeared to be qualitatively similar.

Conclusions: Substantial inhibition of CYP3A- and modest induction of CYP2C9- activity were observed with danoprevir/r and low-dose ritonavir.

Trial registration: ClinicalTrials.gov NCT01185860.

Publication types

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

MeSH terms

  • Adult
  • Antiviral Agents / administration & dosage*
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 CYP3A / metabolism
  • Drug Interactions
  • Drug Therapy, Combination
  • Female
  • Hepatitis C, Chronic / drug therapy
  • Hepatitis C, Chronic / metabolism*
  • Humans
  • Lactams / administration & dosage*
  • Male
  • Midazolam / administration & dosage
  • Midazolam / blood
  • Midazolam / pharmacokinetics*
  • Middle Aged
  • Ritonavir / administration & dosage*
  • Sulfonamides / administration & dosage*
  • Vitamin K / administration & dosage
  • Warfarin / administration & dosage
  • Warfarin / blood
  • Warfarin / pharmacokinetics*
  • Young Adult

Substances

  • Antiviral Agents
  • Lactams
  • Sulfonamides
  • Vitamin K
  • Warfarin
  • danoprevir
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • Ritonavir
  • Midazolam

Associated data

  • ClinicalTrials.gov/NCT01185860