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

Abstract

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.

The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV-1 Maturation

“…An assessment for the potential of 9 to be a perpetrator of drug–drug interactions (DDIs) revealed that the compound was not a potent CYP 450 inhibitor, with IC 50 values of >13.3 μM for CYP 450 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4, of importance for a compound anticipated to be used as part of combination therapy. − There was no evidence of CYP enzyme induction in human hepatocytes with EC 50 values of >5 μM toward CYP 1A2, 2B6, and 3A4. In an in vitro assay, 9 was a weak inhibitor of uridine diphosphate glucuronyltransferase 1A1 (UGT1A1), with an IC 50 of 3.9 μM. − , However, these inhibitory effects have not been manifested in vivo in a clinical study that assessed the effect of 9 on the PK of coadministered dolutegravir, an HIV-1 integrase inhibitor that is a substrate of UGT1A1 …”

“…The mean plasma t 1/2 of 9 was prolonged at 21.2–25.3 h, supportive of a once daily dosing paradigm. The mesylate salt of 9 performed similarly to a bis-HCl salt form, with the former preferred because of better sold-state stability, much reduced moisture uptake, and enhanced solubility . At a dose of 200 mg, there was no significant difference in exposure of 9 from the tablet or capsule form of the mesylate salt form, although there was a 3- to 4-fold increase in exposure when the drug was administered with a meal of moderate fat content.…”

“…While the initial phase of the SAR survey that led to the discovery of 4 had emphasized the uniqueness of the para -substituted benzoic acid moiety incorporated at C-3 of the triterpenoid core, subsequent studies identified the spiro cyclobutene moiety found in 5 and 6 and the cyclohexene that characterizes 7 and 8 as effective scaffolds on which to project the crucial pharmacophoric carboxylic acid moiety (Figure ). − ,, In this article, we describe further studies with 7 and 8 in which the effect of substituents installed α- to the carboxylic acid moiety are explored and led to the discovery of GSK3640254 ( 9 ) as an MI with an optimized antiviral profile that has been advanced into clinical study. ,− …”

Integrating In Vitro Biopharmaceutics into Physiologically Based Biopharmaceutic Model (PBBM) to Predict Food Effect of BCS IV Zwitterionic Drug (GSK3640254)

“…Details for the clinical studies used for the development, qualification and verification of the model can be found elsewhere: FTIH-(ClinicalTrials.gov identifier, NCT03231943) [ 1 ], phase IIa study [ 2 ], food effect study (ClinicalTrials.gov identifier, NCT04263142) [ 11 ] and mass balance Clinical Absorption, Distribution, Metabolism and Excretion (ADME) study [ 12 ].…”

Synthesis, Structure–Activity Relationships, and In Vivo Evaluation of Novel C-17 Amine Derivatives Based on GSK3640254 as HIV-1 Maturation Inhibitors with Broad Spectrum Activity

“…Compound 4 was 86% bound to human plasma proteins using an ultracentrifugation method for measuring protein binding . Compound 4 was advanced into phase I clinical trials to assess safety, tolerability, and pharmacokinetic (PK) properties and was not associated with major tolerability or safety findings. − In a subsequent phase IIa trial to assess efficacy in HIV-1 infected subjects, it was found that a ≥ 1 log 10 median decline in HIV-1 RNA was observed at oral doses of ≥40 mg, and at the highest dose of 200 mg a 2 log 10 median decline in HIV-1 RNA was observed . No major tolerability concerns were noted after the 10-day dosing period.…”