Phase I Evaluation of Pharmacokinetics and Tolerability of the HIV-1 Maturation Inhibitor GSK3640254 and Dolutegravir in Healthy Adults.

AIM: GSK3640254, a novel, next-generation maturation inhibitor effective against a range of HIV polymorphisms with no cross-resistance to current antiretroviral therapy, could potentially be coadministered with dolutegravir as a two-drug regimen. In this phase I study, pharmacokinetics and tolerability of GSK3640254 plus dolutegravir were assessed.
METHODS: Healthy participants received dolutegravir 50 mg once daily (QD) on Days 1-5 in period 1, GSK3640254 200 mg QD on Days 1-7 in period 2, and dolutegravir 50 mg plus GSK3640254 200 mg QD on Days 1-7 in period 3. All treatments were administered with a moderate-fat meal 30 minutes prior to dosing. Pharmacokinetics parameters were derived by noncompartmental methods, and geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were derived using linear mixed effects models. Adverse events, laboratory measurements, electrocardiography, and vital signs were monitored.
RESULTS: Sixteen participants completed the study. GMRs (90% CI) for dolutegravir area under the plasma concentration-time curve from time 0 to the end of the dosing interval at steady state (AUC0-t ), maximum observed concentration (Cmax ), and plasma concentration at the end of the dosing interval (Ct ) were 1.17 (1.118-1.233), 1.09 (1.044-1.138), and 1.24 (1.160-1.315), respectively. GMRs (90% CI) for GSK3640254 AUC0-t , Cmax , and Ct were 1.04 (0.992-1.094), 0.99 (0.923-1.065), and 0.10 (0.939-1.056), respectively. Dolutegravir plus GSK3640254 coadministration did not meaningfully alter steady-state exposure to dolutegravir or GSK3640254. No clinically significant trends in tolerability or safety were observed.
CONCLUSION: Coadministration of GSK3640254 with dolutegravir did not result in clinically significant drug interaction and was well tolerated. This article is protected by copyright. All rights reserved.