PI-011

P. Badri, S. Dutta, A. Asatryan, H. Wang, T. Podsadecki, W. Awni, R. Menon; AbbVie Inc., North Chicago, IL

BACKGROUND: The all-oral IFN-free, 3 direct acting antiviral (DAA) combination regimen (3D) of ABT-450/r (NS3 protease inhibitor identified by AbbVie and Enanta coadministered with ritonavir), ombitasvir (NS5A inhibitor) and dasabuvir (NS5B polymerase inhibitor) ± ribavirin has been evaluated in 6 Phase III clinical trials in HCV genotype 1-infected subjects. This study assessed pharmacokinetics, safety and tolerability of coadministration of a strong CYP3A4 inducer, carbamazepine (CBZ), with the 3D regimen.
METHODS: Single doses of the 3D regimen (ABT-450/r/ombitasvir 150/100/25 mg + dasabuvir 250 mg) were administered alone and in the presence of steady state CBZ 200 mg BID in 12 healthy subjects. Drug concentrations were determined from blood samples collected on multiple study days and PK parameters were estimated by non-compartmental analyses. Safety was assessed (adverse events, vital signs, ECG, etc.) throughout the study.
RESULTS: In the presence of CBZ, ABT-450, ritonavir, ombitasvir and dasabuvir exposures (Cmax and AUC) decreased by 66% - 71%, 83% - 88%, 30% - 32% and 55% - 70%, respectively. CBZ exposures were minimally affected (17% increase). Coadministration of the 3D with CBZ was generally tolerated by the subjects. More treatment-emergent adverse events of nausea and vomiting considered related to CBZ were reported compared to 3D alone. Increases in ALT and AST were observed when 3D was coadministered with CBZ, peaking at Grade 3 in 1 subject.
CONCLUSION: Significant decreases were observed in ABT-450, ritonavir and dasabuvir exposures in the presence of a strong CYP3A4 inducer, CBZ, which could lead to decreases in the therapeutic activity of the 3D regimen. Thus, coadministration of the 3D regimen with strong enzyme inducers such as carbamazepine is not recommended.