European Journal of Clinical Pharmacology

, Volume 69, Issue 11, pp 1939–1949

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

  • Peter N. Morcos
  • Linda Chang
  • Rohit Kulkarni
  • Mylene Giraudon
  • Nancy Shulman
  • Barbara J. Brennan
  • Patrick F. Smith
  • Jonathan Q. Tran
Pharmacokinetics and Disposition

DOI: 10.1007/s00228-013-1556-y

Cite this article as:
Morcos, P.N., Chang, L., Kulkarni, R. et al. Eur J Clin Pharmacol (2013) 69: 1939. doi:10.1007/s00228-013-1556-y

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.

Keywords

CYP3ADanoprevirMidazolamRitonavirWarfarin

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Peter N. Morcos
    • 1
  • Linda Chang
    • 2
    • 6
  • Rohit Kulkarni
    • 3
  • Mylene Giraudon
    • 4
  • Nancy Shulman
    • 5
  • Barbara J. Brennan
    • 1
  • Patrick F. Smith
    • 1
    • 7
    • 8
  • Jonathan Q. Tran
    • 2
    • 9
  1. 1.Hoffmann-La Roche Inc.NutleyUSA
  2. 2.Hoffmann-La Roche Inc.Palo AltoUSA
  3. 3.Guardian AnalyticsMountain ViewUSA
  4. 4.F. Hoffmann-La Roche LtdBaselSwitzerland
  5. 5.GenentechSouth San FranciscoUSA
  6. 6.MedImmune LLCHaywardUSA
  7. 7.d3 LimitedMontvilleUSA
  8. 8.University at Buffalo School of PharmacyBuffaloUSA
  9. 9.Biogen IdecCambridgeUSA