A Phase 1 Study to Assess the Relative Bioavailability, Food Effect, and Safety of a Tablet Formulation of GSK2838232, a Novel HIV Maturation Inhibitor in Healthy Participants After Single and Repeated Doses

Abstract

GSK2838232 is a novel, potent HIV-1 maturation inhibitor for use in regimen-based combination antiretroviral therapy from a once-daily oral dose boosted with a pharmacoenhancer (ritonavir or cobicistat). This phase 1 study in healthy participants was conducted in 2 parts. Part 1 (n = 14) assessed the relative bioavailability of single doses of a 200-mg GSK2838232 tablet and capsule formulation boosted with 100 mg ritonavir in fed and fasted (tablet-only) subjects. Part 2 (n = 10) assessed the pharmacokinetics of repeated 500-mg once-daily doses of GSK2838232 without a pharmacoenhancing boosting agent. In part 1, GSK2838232 demonstrated comparable bioavailability following a single dose of 200 mg GSK2838232 as capsule and tablet formulations in combination with ritonavir (RTV) under fed conditions, with lower intrasubject variability observed for the tablet formulation. In part 2, following administration of 500 mg GSK2838232 once daily for 11 days under fed conditions, C max , AUC 0-τ , and Cτ showed a small degree of accumulation (1.2-to 1.3-fold) of GSK2838232. The median t max was approximately 4 hours on both day 1 and day 11 when given with food. The mean t 1 2 was approximately 23 hours on day 11. Steady-state concentrations were achieved by day 3 with a geometric mean steady-state Cτ on day 11 of 28 ng/mL. The tablet formulation was generally well tolerated as a single 200-mg dose with RTV under fed and fasted conditions and following administration of multiple daily doses (11 days) of 500 mg unboosted.

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

“…Compared with administration under fasted conditions, administration of GSK3640254 under high‐ and moderate‐fat conditions resulted in a 3‐ to 4‐fold increase in mean peak and total plasma exposures (geometric mean ratios between 2.59 and 4.10). This increase in plasma exposure with the coadministration of food is similar to observations from another MI study 13 . Relative to fasted conditions, increases in peak (C max ) and total (AUC 0‐∞ and AUC 0‐t ) plasma exposures appeared to be greater under moderate‐fat conditions (geometric mean ratios between 2.93 and 4.10) than high‐fat conditions (geometric mean ratios between 2.59 and 3.08).…”

“…This increase in plasma exposure with the coadministration of food is similar to observations from another MI study. 13 Relative to fasted conditions, increases in peak (C max ) and total (AUC 0‐∞ and AUC 0‐t ) plasma exposures appeared to be greater under moderate‐fat conditions (geometric mean ratios between 2.93 and 4.10) than high‐fat conditions (geometric mean ratios between 2.59 and 3.08). However, this study was not specifically designed to compare increases in exposures between moderate‐ and high‐fat meals.…”

A phase I, first‐in‐human study investigating the safety, tolerability, and pharmacokinetics of the maturation inhibitor GSK3739937

“…Similar to the structurally related GSK'3640254, 21 GSK'937 was well‐tolerated and did not cause any significant changes to clinical laboratory analyses. GSK'937 was also slowly metabolized, with a t 1/2 of approximately 3 days, suggesting a possible QW dosing strategy, distinguishing GSK'937 from previous developmental MIs that have half‐lives supportive of daily dosing 20,21,23 . Higher plasma concentrations were achieved when GSK'937 was administered as a tablet compared to PiB and when delivered with a meal instead of after fasting.…”

Are Myths and Preconceptions Preventing Us from Applying Ionic Liquid Forms of Antiviral Medicines to the Current Health Crisis?

“…This reverse transcriptase maturation inhibitor was found to be potent against a broad range of clinically relevant sequences of major structural proteins of HIV virus (group-specific antigens or gags). As an API, GSK2838232 successfully passed Phase I clinical studies [99] and is currently in phase II clinical trials [100] for the treatment of HIV infections. ) have been shown to be successfully loaded onto silica [93], and can be released from it in different media when necessary.…”

“…This reverse transcriptase maturation inhibitor was found to be potent against a broad range of clinically relevant sequences of major structural proteins of HIV virus (group-specific antigens or gags). As an API, GSK2838232 successfully passed Phase I clinical studies [99] and is currently in phase II clinical trials [100] for the treatment of HIV infections. The API, however, presented issues with solubility (<0.01 µ g/ mL), where the particle/suspension settling risk could potentially lead to caking, particle growth and/or agglomeration, resuspension challenges, particulate clogging of syringes, etc.…”