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.

Keywords: HIV-1 infection; bioavailability; clinical study; first-time-in-human; healthy participants; pharmacokinetics; safety.

Figure 1

Original study design of the single and multiple ascending dose study. A/P, active treatment/placebo; QD, once daily. Cohort 1 required four replacement participants to undergo randomization to complete the remainder of the periods. Cohort 6 and the expansion cohort required one replacement participant each to undergo randomization and complete the treatment period

Figure 2

Mean (95% CI) plasma concentration of GSK3640254 in linear and semi‐log scale in the single‐dose part of the ascending dose study. The horizontal dashed line represents the lower limit of detection for the assay

Figure 3

Mean (95% CI) plasma concentration of GSK3640254 in linear and semi‐log scale in the multiple‐dose part of the ascending dose study (Days 1 and 14). The horizontal dashed line represents the lower limit of detection for the assay. ^†Includes participants from cohort 5 and the expansion cohort

Figure 4

Plasma GSK3640254 predose daily concentration troughs over time for all participants in Part 2 in the (A) 50‐mg, (B) 100‐mg, (C) 200‐mg, and (D) 320‐mg cohorts. ^aPredose (trough) concentrations shown for Days 1‐14; last dose was taken on Day 14. Days 15‐18 are follow‐up visits. ^bLower limit of quantification equals 3 ng/mL

Figure 5

Mean (95% CI) plasma concentration of GSK3640254 in linear scale in the relative bioavailability study