Phase I evaluation of the safety, tolerability, and pharmacokinetics of GSK3640254, a next‐generation HIV‐1 maturation inhibitor

Joshi²,

et al. 2021

Brit J Clinical Pharma

Self Cite

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

Section: Discussionsupporting

confidence: 89%

“…This value is similar to a t 1/2 value for GSK3640254 administered alone that was reported in a previous study on Day 14 of treatment (22.1 h). 7 …”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Joshi²,

et al. 2021

Brit J Clinical Pharma

Self Cite

“…GSK3640254 is a novel, next-generation MI that blocks the final protease cleavage event between CA protein p24 and CA-spacer 1, resulting in noninfectious virions ( 7 ). GSK3640254 has no cross-resistance to currently approved classes, is effective against a broad range of Gag polymorphisms, and has a preclinical profile that supports clinical evaluation for treatment of HIV-1 infection.…”

Section: Textmentioning

confidence: 99%

A Phase I Evaluation of the Pharmacokinetics and Tolerability of the HIV-1 Maturation Inhibitor GSK3640254 and Tenofovir Alafenamide/Emtricitabine in Healthy Participants

Antimicrob Agents Chemother

Joshi²,

et al. 2021

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Introduction: GSK3640254 is a next-generation maturation inhibitor that would likely be combined with standard antiretroviral agents to form a regimen of ≥2 fully active classes. Methods: This phase I, open-label, 2-period, 1-way study assessed potential pharmacokinetic (PK) interactions between GSK3640254 and tenofovir alafenamide/emtricitabine (TAF/FTC; including the metabolite tenofovir [TFV]) in healthy volunteers. Eligible participants received TAF/FTC 25/200 mg once daily (QD) on Days 1 through 21 with a moderate-fat meal; GSK3640254 200 mg QD was added on Days 15 through 21. Geometric least squares mean ratios (GMRs) and 90% CIs were derived using linear mixed-effect models. Adverse events (AEs) and laboratory, electrocardiogram, and vital sign parameters were monitored. Results: Sixteen participants, all male, received treatment; one withdrew because of treatment-related grade 1 urticaria. After TAF/FTC + GSK3640254 coadministration, TAF steady-state area under the plasma concentration-time curve from time 0 to the end of the dosing interval and maximum observed concentration were 11% and 13% lower than when TAF/FTC was administered alone, with GMR (90% CI) of 0.886 (0.75-1.04) and 0.874 (0.68-1.12), respectively. Steady-state PK of TFV and FTC was similar when TAF/FTC was administered alone or with GSK3640254. No clinically significant trends in tolerability or safety were observed. Conclusions: GSK3640254 200 mg QD did not meaningfully affect the steady-state PK of TAF, TFV, or FTC in healthy participants under fed conditions and was not associated with major tolerability or safety findings. These data support the further investigation of GSK3640254 for coadministration with TAF/FTC for the treatment of HIV (ClinicalTrials.gov, NCT03836729).

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

Johnson¹,

Clinical Pharm in Drug Dev

Joshi³

et al. 2022

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GSK3640254 is a next-generation maturation inhibitor with demonstrated potency across HIV-1 subtypes and a high barrier to emergent resistance. This phase I, 2-part, randomized, open-label study (ClinicalTrials.gov identifier, NCT04263142) in healthy participants assessed the relative bioavailability of a single dose of GSK3640254 200 mg in tablet and capsule formulations (part 1) and the effect of food on the pharmacokinetic profile of the tablet formulation (part 2). Overall, 39 participants were randomized to treatment (part 1, n = 18; part 2, n = 21). All participants in part 1 completed the study; 2 participants in part 2 withdrew before study completion (adverse event, n = 1; physician decision, n = 1). In part 1, plasma exposures of the GSK3640254 tablet formulation were not meaningfully different from those of the capsule formulation when administered in the presence of a moderate-fat meal. In part 2, GSK3640254 plasma exposures increased by ≈3to 4-fold under high-and moderate-fat conditions, respectively, compared with fasted conditions. No major safety or tolerability findings were observed. The highest incidence of adverse events (24%) was reported under high-fat conditions. Taken together, these data support the use of the tablet formulation coadministered with food in the clinical development of GSK3640254 for treatment of HIV-1.