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

• Published in: European journal of clinical pharmacology Vol. 69; no. 11; pp. 1939 - 1949
• Main Authors: Morcos, Peter N., Chang, Linda, Kulkarni, Rohit, Giraudon, Mylene, Shulman, Nancy, Brennan, Barbara J., Smith, Patrick F., Tran, Jonathan Q.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.11.2013; Springer; Springer Nature B.V
• Subjects: Adult; Antiviral Agents - administration & dosage; Aryl Hydrocarbon Hydroxylases - metabolism; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Clinical trials; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP3A - metabolism; Drug Interactions; Drug therapy; Drug Therapy, Combination; Female; Hepatitis; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - metabolism; Human viral diseases; Humans; Infectious diseases; Lactams - administration & dosage; Male; Medical sciences; Midazolam - administration & dosage; Midazolam - blood; Midazolam - pharmacokinetics; Middle Aged; Pharmacokinetics and Disposition; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Ritonavir - administration & dosage; Sulfonamides - administration & dosage; Viral diseases; Viral hepatitis; Vitamin K - administration & dosage; Warfarin - administration & dosage; Warfarin - blood; Warfarin - pharmacokinetics; Young Adult; Danoprevir; CYP3A; Warfarin; Midazolam; Ritonavir; Antiretroviral agent; Isozyme; Psychotropic; Coumarine derivatives; Hepatic disease; Anticoagulant; Antivitamin K; Randomization; Benzodiazepine derivatives; Antiviral; Sedative; Viral hepatitis C; Human; Drug; Enzyme; Cytochrome P450; Enzyme inhibitor; Hypnotic; Infection; Substrate; Peptidases; Viral disease; Hydrolases; Digestive diseases; Protease inhibitor
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-013-1556-y

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 (AUC 0–∞ ) and reduced the midazolam metabolic ratio while S-warfarin AUC 0–∞ was modestly decreased. When danoprevir data were pooled across doses, the midazolam GMR (90 % CI) AUC 0–∞ 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) AUC 0–∞ 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.