P. Badri, S. Dutta, L. Rodrigues, Jr, B. Ding, T. 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 (protease inhibitor identified by AbbVie and Enanta, dosed with ritonavir), ombitasvir (NS5A inhibitor) and dasabuvir (NS5B polymerase inhibitor) ± ribavirin (RBV) has been evaluated in six Phase III trials in HCV genotype (GT) 1 infected subjects. The 2D (ABT-450/r + ombitasvir) ± RBV has been evaluated in HCV GT1b/4 infected subjects. This study assessed PK, safety and tolerability of co-administration of a model P-glycoprotein substrate (P-gp), digoxin, with 3D or 2D.
METHODS: Single doses of digoxin (0.5 mg) were administered alone and in presence of steady state ABT-450/r 150/100 mg QD + ombitasvir 25 mg QD +/- dasabuvir 400 mg BID in 24 healthy volunteers. Drug concentrations were determined from intensive blood samples collected on multiple study days and PK parameters were estimated by non-compartmental analyses. Safety was assessed (adverse events, vital signs, ECG and clinical laboratory tests) throughout the study.
RESULTS: Following coadministration with the 3D or 2D regimens, digoxin exposures (Cmax and AUCinf) increased by 15-16% (3D) and 24-58% (2D). DAA exposures were not affected (≤ 15% change). Regimens were well tolerated in the studied sample. The safety profile of DAAs with digoxin is comparable to that when the DAAs are administered alone.
CONCLUSION: Digoxin exposures increase slightly (≤ 16%) with 3D while clinically relevant increases (≤ 58%) were observed with 2D. Since digoxin is a narrow therapeutic index (NTI) drug, subjects receiving this drug in combination with 2D or 3D should be monitored, with 30-50% dose decrease recommended with 2D. Since 3D does not cause meaningful P-gp inhibition, P-gp substrates do not require dose adjustment with 3D.