J. M. Custodio, H. Wang, A. Silva, L. Zhong, J. Z. Zack, C. Callebaut, S. McCallister, B. P. Kearney, S. Ramanathan; Gilead Sciences, Foster City, CA
BACKGROUND: TAF, a new antiretroviral agent with a favorable pharmacokinetic (PK) and safety profile vs. TFV disoproxil fumarate, has been coformulated with FTC into the fixed dose combination F/TAF. This study evaluated the drug interaction potential of F/TAF (200/25 mg; the highest clinical TAF dose) and DRV/COBI (800/150 mg; their respective labeled doses).
METHODS: Cohort 1 subjects (n=12) received F/TAF for 12 days then F/TAF + DRV/COBI for 12 days. Cohort 2 subjects (n=14) received DRV/COBI for 10 days then F/TAF + DRV/COBI for 12 days. Intensive PK was collected on the last day of each treatment. Statistical comparisons were geometric mean ratios (GMR) and associated no-effect 90% confidence intervals (CI) of 70-143% based upon previously defined safe and efficacious exposure ranges of these agents. TAF PK was also assessed on Days 1 and 13 in Cohort 1. Safety was assessed throughout.
RESULTS: All treatments were well-tolerated and the only adverse event related to discontinuation was unrelated to study drug (Grade 2 joint abscess). Following F/TAF + DRV/COBI, the 90% CIs of the GMRs for FTC, DRV and COBI were within 70-143%, vs. F/TAF or DRV/COBI alone. An increase in TAF exposure (AUC 63% higher) following a single-dose of F/TAF + DRV/COBI, vs. a single-dose of F/TAF alone, was not observed upon multiple-dosing (GMR (90% CI): 97.6 (80.4-119), presumably due to a mixed inhibitory/inductive effect of DRV/COBI on P-gp affecting TAF absorption. Following F/TAF + DRV/COBI, TFV AUC was increased 3.2-fold, vs. F/TAF alone, consistent with historical data following administration of TAF + COBI only.
CONCLUSION: Administration of F/TAF + DRV/COBI did not alter FTC, DRV, and COBI exposures but 3.2-fold higher TFV exposure was observed, vs. F/TAF or DRV/COBI alone. TAF exposures were comparable across treatments.