Two-way interaction study using ritonavirboosted danoprevir, a potent HCV protease inhibitor, and ketoconazole in healthy subjects

Background: Danoprevir is a potent, highly selective, macrocyclic, orally bioavailable inhibitor of the hepatitis C virus protease, and a substrate of cytochrome P450 (CYP) 3A. It is co-administered with low-dose ritonavir, a potent CYP3A inhibitor, to enhance danoprevir pharmacokinetics. Ketoconazole is a substrate for and potent selective inhibitor of CYP3A. Methods: In this open-label, 3-period study, the 2-way interaction potential between ritonavir-boosted danoprevir (danoprevir/r) and ketoconazole was investigated in 18 healthy subjects. Subjects initially received ketoconazole 200 mg q24h for 4 days (period 1) followed by a 7-day washout period. Danoprevir/r 100/100 mg q12h was then given for 10 days (period 2) followed by a further 4 days of danoprevir/r 100/100 mg q12h plus ketoconazole 200 mg q24h (period 3). Serial blood samples were collected for the determination of danoprevir, ritonavir and/or ketoconazole plasma concentrations, and calculation of pharmacokinetic parameters. Safety and tolerability were monitored throughout the study. Results: Co-administration of ketoconazole with danoprevir/r modestly increased the danoprevir AUC_t by 1.44-fold, with no effect on danoprevir C _max. Co-administration of danoprevir/r with ketoconazole substantially increased ketoconazole AUC_t and C_max by 3.71-fold and 1.73-fold, respectively. Danoprevir/r was well tolerated when administered alone or with ketoconazole. Conclusions: These results indicate that the effect of potent CYP3A inhibitors, such as ketoconazole, on danoprevir/r pharmacokinetics is not likely to be clinically relevant.