Phase I evaluation of pharmacokinetics and tolerability of the HIV‐1 maturation inhibitor GSK3640254 and dolutegravir in healthy adults

Abstract

range of HIV polymorphisms with no cross-resistance to current antiretroviral therapy, could potentially be coadministered with dolutegravir as a 2-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% CIs) for dolutegravir area under the plasma concentration-time curve from time 0 to the end of the dosing interval at steady state, maximum observed concentration and plasma concentration at the end of the dosing interval were 1.17 (1.118-1.233), 1.09 (1.044-1.138) and 1.24 (1.160-1.315), respectively. The GMRs (90% CIs) for GSK3640254 were 1.04

Lack of pharmacokinetic interaction between the HIV‐1 maturation inhibitor GSK3640254 and combination oral contraceptives in healthy women

“…Ethinyl oestradiol‐containing oral contraceptives were also associated with elevated liver transaminases in a 2018 study 20 . Further, an AE of increased transaminases was reported in only 1 of 63 healthy participants who received GSK3640254 200 mg across 3 other phase I studies 9,21,22 …”

Relative Bioavailability and Food Effect of GSK3640254 Tablet and Capsule Formulations in Healthy Participants

“…In the phase IIa proof‐of‐concept study in treatment‐naive adults with HIV‐1 (NCT03784079), the GSK3640254 200‐mg dose resulted in an approximately 2‐log 10 reduction in plasma HIV‐1 RNA with no noted safety or tolerability concerns 6 . GSK3640254 is an inhibitor of uridine diphosphate glucuronosyltransferase 1A1 and organic anion‐transporting polypeptide 1B3 in vitro 7,8 . Drug interaction studies have demonstrated no meaningful effect of GSK3640254 on the pharmacokinetics of dolutegravir, tenofovir alafenamide, or combined oral contraceptives 7–9 …”

“…6 GSK3640254 is an inhibitor of uridine diphosphate glucuronosyltransferase 1A1 and organic anion-transporting polypeptide 1B3 in vitro. 7,8 Drug interaction studies have demonstrated no meaningful effect of GSK3640254 on the pharmacokinetics of dolutegravir, tenofovir alafenamide, or combined oral contraceptives. [7][8][9] In both phase I and phase IIa proof-of-concept studies, GSK3640254 was formulated as a mesylate salt in a capsule.…”

“…7,8 Drug interaction studies have demonstrated no meaningful effect of GSK3640254 on the pharmacokinetics of dolutegravir, tenofovir alafenamide, or combined oral contraceptives. [7][8][9] In both phase I and phase IIa proof-of-concept studies, GSK3640254 was formulated as a mesylate salt in a capsule. 5,6 In planned phase IIb studies, the proposed formulation for GSK3640254 is a mesylate salt in a tablet.…”

Highlights from the virtual conference on retroviruses and opportunistic infections (CROI) 2021: SARS-CoV-2 pathogenesis, new data about antiretroviral treatments, HIV-associated comorbidities, pediatrics and pregnancy

“…However, a published phase 1 study investigating the pharmacokinetics of GSK254 and dolutegravir has concluded that “these agents could be used in combination for the treatment of HIV infection, in particular as part of a fixed‐dose, 2‐drug regimen” so presumably this is another direction of travel for GSK-254. 13 …”