title: 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.
abstract: OBJECTIVE
  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.
authors.affiliation: Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ, 07110, USA, peter.morcos@roche.com.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Morcos
authors.forename: Linda
authors.initials: L
authors.lastname: Chang
authors.forename: Rohit
authors.initials: R
authors.lastname: Kulkarni
authors.forename: Mylene
authors.initials: M
authors.lastname: Giraudon
authors.forename: Nancy
authors.initials: N
authors.lastname: Shulman
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Brennan
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Smith
authors.forename: Jonathan Q
authors.initials: JQ
authors.lastname: Tran
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D003521:Cyclopropanes; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D054833:Isoindoles; D007769:Lactams / Q000008:administration & dosage*; D047029:Lactams, Macrocyclic; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D011392:Proline / Q000031:analogs & derivatives; D019438:Ritonavir / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage*; D014812:Vitamin K / Q000008:administration & dosage; D014859:Warfarin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D013449:Sulfonamides; D014812:Vitamin K; D014859:Warfarin; C553752:danoprevir; D011392:Proline; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D019438:Ritonavir; D008874:Midazolam