Effect of rifabutin on the pharmacokinetics of oral cabotegravir in healthy subjects.

BACKGROUND: Cabotegravir (CAB) is an integrase strand transfer inhibitor in development as a long-acting injectable formulation, with an oral formulation used during a safety lead-in period. Tuberculosis (TB)/HIV co-infection is common, often requiring simultaneous treatment. Rifabutin (RBT) is an alternative antimycobacterial agent for TB and a moderate inducer of cytochrome P450 and UDP-glucuronosyltransferase isoenzymes. This study evaluated the impact of RBT on the pharmacokinetics (PK) of oral CAB.

METHODS: In this Phase 1, single-center, open-label, two-period, fixed-sequence, drug interaction study, subjects received oral CAB 30mg once daily (QD) for 14 days in Period 1, and oral CAB plus RBT 300mg QD for 14 days in Period 2. Serial PK sampling was performed on Days 14 and 28. Geometric least squares (GLS) mean ratios with associated 90% CIs were calculated to compare CAB noncompartmental PK parameters following CAB+RBT vs. CAB alone. Safety was also assessed.

RESULTS: Fifteen male subjects were enrolled and 12 completed all treatments. Comparing CAB+RBT with CAB alone, the GLS mean ratios (90% CIs) for CAB AUC0-τ , Cmax , and Cτ were 0.79 (0.74, 0.83), 0.83 (0.76, 0.90), and 0.74 (0.70, 0.78), respectively. Eleven subjects reported 24 adverse events (AEs); 22 were reported with CAB+RBT (three drug-related), and two with CAB alone (not drug-related). All AEs resolved by study end.

CONCLUSIONS: RBT had a modest impact on plasma CAB exposure following oral co-administration, resulting in overall plasma CAB trough exposures above the 10mg oral dose shown to maintain viral suppression in HIV-1-infected subjects. Oral CAB can be co-administered with RBT without dosage adjustment.