T. Wang, S. Dutta, E. Coakley, U. Das, T. J. Podsadecki, W. Awni, R. Menon; AbbVie Inc., North Chicago, IL
BACKGROUND: The all-oral IFN-free, 3 direct acting antiviral (DAA) combination (3D) of ABT-450/r (NS3 protease inhibitor identified by AbbVie and Enanta, coadministered with ritonavir) + ombitasvir (NS5A inhibitor) + dasabuvir (NS5B polymerase inhibitor) and 2D regimen (ABT-450/r + ombitasvir) ± ribavirin has been evaluated in HCV genotype (GT) 1 and GT1b/4-infected subjects, respectively. This study assessed pharmacokinetics (PK), safety and tolerability of coadministration of the strong CYP3A4 & P-gp inhibitor, ketoconazole (KTZ), with 3D or 2D.
METHODS: Single doses of ABT-450/r/ ombitasvir 150/100/25 mg +/- dasabuvir 250 mg were administered alone and in the presence of steady state KTZ 400 mg QD in 24 healthy volunteers. Drug concentrations were determined from intensive blood samples and PK parameters were estimated by non-compartmental analyses. Safety assessment (adverse events, clinical labs, vital signs, ECG) was done throughout the study.
RESULTS: KTZ increased the ABT-450 Cmax and AUCinf by 37-72% and 98-116%. Exposures of ritonavir, ombitasvir, and dasabuvir were increased by 27-57%, up to 26%, and up to 42%, respectively. Following coadministration with a single dose of 3D or 2D, KTZ Cmax was comparable (<20% change) while AUC24 increased by 105-117% compared to administration alone, due to decrease in KTZ clearance. In this study with 12 subjects/group, the regimens were well tolerated over the 1-day coadministration.
CONCLUSION: KTZ doses should be limited to less than 200 mg per day during coadministration with 3D or 2D. Changes in exposures of ABT-450, ombitasvir, dasabuvir, and ritonavir are not considered clinically significant and no dose adjustments are recommended when the 3D or 2D regimen is coadministered with CYP3A4 inhibitors or Pgp inhibitors.