The safety, tolerability, and pharmacokinetic profile of GSK2838232, a novel 2nd generation HIV maturation inhibitor, as assessed in healthy subjects

Abstract

This work aimed to assess the safety, tolerability, pharmacokinetics (PK), and relative bioavailability of GSK2838232, an investigational HIV maturation inhibitor. GSK2838232 was administered over four dose‐escalation studies in healthy subjects which assessed single oral doses (5‐250 mg) and repeat doses (up to 200 mg once or twice daily) ±100 mg ritonavir (RTV) once daily. GSK2838232 administration (up to 250 mg) to 124 subjects across four studies resulted in few mild adverse events (AEs) with similar frequencies to placebo. There were no clearly identified drug‐related AEs. GSK2838232 tested fasted was quickly absorbed with a t max of 2‐3 hours. With food, the absorption was delayed and more variable, with ~60% increase in AUC and C max. Overall, following single doses GSK2838232 AUC and C max generally exhibited proportional PK from 50 to 100 mg dose without RTV and from 50 to 250 mg with RTV and following repeated doses of 20‐200 mg with RTV. In relative bioavailability studies, a micronized formulation was found to be suitable for development. At steady state, RTV increased GSK2838232 AUC and C max by 10‐ and 3‐fold, respectively. Half‐life was prolonged from ~17 hours nonboosted to ~34 hours with RTV. This boosting effect was also seen in repeat‐dose GSK2838232 studies, which achieved the targeted plasma exposure with GSK2838232 as a once‐daily regimen of up to 200 mg with RTV. The results of these studies demonstrated a favorable safety and PK profile for GSK2838232 and support its investigation for the treatment of HIV infection.

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

“…HIV-1. However, based on the results from a previous MI study in which women were enrolled, 7 we do not anticipate differences in PK properties due to gender. Women of childbearing potential were not eligible for study participation because the effect of GSK3640254 on fetal development was unknown during the conduct of the trial.…”

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

“…GSK2838232 was safe and well tolerated in previous healthy volunteer studies as single and repeat doses, alone or in combination with RTV, with or without food and has demonstrated antiviral activity in a phase 2a study in HIV-infected patients. 3,4 In these initial trials in healthy subjects, GSK2838232 was quickly absorbed, with t max in the order of 2-3 hours when administered in the fasted state. In the fed state (high-fat meal), the absorption was delayed and more variable.…”

“…Maturation inhibitors (MIs) represent a new class of compound for the treatment of HIV infection, distinct from viral entry, protease, reverse transcriptase, or integrase inhibitors 2 . GSK2838232 is a novel HIV‐1 MI being developed for HIV‐1 treatment in combination with antiretroviral therapy 3 . GSK2838232 has potent antiviral activity in vitro, with a mean 50% maximal inhibitory concentration (IC 50 ) of 1.6 nM and retains activity across a broad spectrum of HIV isolates, including polymorphic GAG sequences that were problematic for earlier drug candidates.…”

Recent advances in natural anti‐HIV triterpenoids and analogs

“…In clinical studies, GSK2838232 (100 and 200 mg) with 100 mg ritonavir for 11 days exhibited good safety but was significantly influenced by CYP3A4 and P-gp inhibitors. 54 Recently, conjugations between betulinic acid/betulin and AZT have been reported. One-pot synthesis of ester-linked conjugates of betulinic acid with AZT and its derivatives or with 3TC was accomplished.…”

“…Furthermore, GSK2838232 ( 45 ), the only α‐keto amide betulin derivative investigated in a Phase I clinical study, had low to moderate relative bioavailability (6%–40%) and was metabolized through hepatic Phase I oxidation, Phase II glucuronidation and biliary excretion, according to these preclinical studies. In clinical studies, GSK2838232 (100 and 200 mg) with 100 mg ritonavir for 11 days exhibited good safety but was significantly influenced by CYP3A4 and P‐gp inhibitors 54 …”