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

ABSTRACT: Despite advances in HIV-1 management with antiretroviral therapy, drug resistance and toxicities with multidrug regimens can result in treatment failure. Hence, there is a continuing demand for antiretroviral agents (ARVs) with novel mechanisms of action. Maturation inhibitors inhibit HIV-1 replication via a unique mechanism of action and can be combined with other ARVs. Two phase I randomized clinical trials were conducted for a maturation inhibitor, GSK3640254, to determine safety, pharmacokinetics (NCT03231943), and relative bioavailability (NCT03575962) in healthy adults. The first trial was conducted in two parts. Part 1 was conducted in a two-cohort, interlocking, eight-period fashion in 20 participants with single ascending doses of GSK3640254 (1-700 mg) or placebo. In Part 2, 58 participants were randomized to receive GSK3640254 (n = 44) or placebo (n = 14). Four participants reported adverse events (AEs) leading to study discontinuation, with one adverse drug reaction (maculopapular rash). There was no relationship between frequency or severity of AEs and dose. Pharmacokinetic assessments showed that GSK3640254 was slowly absorbed, with time to maximum concentration (tmax) occurring between 3.5 and 4 hours and half-life of ~24 hours. In the relative bioavailability study of GSK3640254 mesylate salt vs bis-hydrochloride salt capsules in 14 healthy adults, the mesylate salt performed slightly better than the bis-hydrochloride formulation (12%-16% increase in area under the concentration-time curve and maximum concentration); tmax (5 hours) was similar between the formulations. Initial pharmacokinetic and safety data from these healthy-participant studies informed further development of GSK3640254 for once-daily dosing for the treatment of HIV-1 infection.

SUBMITTER: Joshi SR

PROVIDER: S-EPMC7670640 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Joshi Samit R SR Fernando Disala D Igwe Stephanie S McKenzie Litza L Krishnatry Anu S AS Halliday Fiona F Zhan Joyce J Greene Thomas J TJ Xu Jianfeng J Ferron-Brady Geraldine G Lataillade Max M Min Sherene S

Pharmacology research & perspectives 20201201 6

Despite advances in HIV-1 management with antiretroviral therapy, drug resistance and toxicities with multidrug regimens can result in treatment failure. Hence, there is a continuing demand for antiretroviral agents (ARVs) with novel mechanisms of action. Maturation inhibitors inhibit HIV-1 replication via a unique mechanism of action and can be combined with other ARVs. Two phase I randomized clinical trials were conducted for a maturation inhibitor, GSK3640254, to determine safety, pharmacokin ...[more]

PMID: 33200887

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Project description:BACKGROUND: Preclinical studies have demonstrated that pharmacological mobilization and recruitment of endogenous bone marrow stem cells and immunoregulatory cells by a combination of plerixafor and low-dose tacrolimus (MRG-001) improves wound healing, promotes tissue regeneration and prevents allograft rejection. This first‐in‐human phase I dose‐escalation study evaluates the safety, tolerability, pharmacokinetics and pharmacodynamics of MRG-001, a novel fixed-dose combination drug. METHODS: In this Phase 1, double‐blind, randomized, placebo-controlled study, multiple ascending dose (MAD) cohorts are randomized to receive MRG-001 containing up to 0.02 mL/kg (plerixafor 24 mg/mL and tacrolimus 0.5 mg/mL) or saline placebo, subcutaneously every other day (SC, QAD) for 5 days (ClinicalTrials.gov: NCT04646603)The primary outcome is safety and tolerability. Safety and functional assessments are performed throughout the study. Blood samples are collected to evaluate systemic exposure. Fluorescence-activated cell sorting analysis and RNA expression of peripheral blood mononuclear cells (PBMCs) are used to evaluate the pharmacodynamics. RESULTS: Fourteen subjects received MRG-001 and 7 received a placebo. MRG-001 is safe and well-tolerated over the selected dose range. No deaths or severe adverse events are reported. There are no clinically significant laboratory changes after MRG-001 administration, apart from the predicted generalized leukocytosis. The intermediate dose group (0.01 mL/kg) showed the most significant white blood cell mobilization over time and increased by 2-4 fold from baseline and returned to baseline levels prior to the next injection. Circulating immune cells including FOXP3+ regulatory T cells and hematopoietic stem cells (CD45IntCD34+) increased significantly after MRG-001 injection. PBMC RNA sequencing and gene set enrichment analysis revealeds 31 down-regulated pathways in the intermediate dose MRG-001 group compared to no changes in the placebo group. CONCLUSION: MRG-001 is safe and well-tolerated across the full dose ranges tested. MRG-001 may be a clinically useful therapy for immunoregulation and tissue regeneration. A Phase II trial to treat severely and critically ill COVID-19 patients with MRG-001 has been initiated (NCT04646603) and a second phase II trial will explore the potential of MRG-001 to accelerate wound healing (NCT05844527),

Dataset Information

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

Publications

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

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