Open‐label, drug–drug interaction study between the HIV‐1 maturation inhibitor GSK3640254 and a metabolic probe cocktail in healthy participants

Abstract

Aims GSK3640254 (GSK'254) is an HIV‐1 maturation inhibitor with pharmacokinetics (PK) supporting once‐daily dosing. GSK'254 will be co‐administered with cytochrome P450 enzyme substrates and drug transporters, including other antiretrovirals, in people living with HIV‐1 (PLWH). Methods In this open‐label study, healthy participants received a single dose of a cocktail of eight cytochrome P450 and transporter probe substrates on Day 1, followed by a 10‐day washout before receiving GSK'254 200 mg once daily from Days 11 to 20 and a single dose of cocktail + GSK'254 200 mg on Day 21. Geometric least‐squares mean ratios and 90% confidence intervals were obtained using linear mixed‐effects models. Adverse events (AEs) were monitored. Results Of 20 participants enrolled, 19 completed the study. Plasma concentrations of all cocktail substrates were generally similar with or without GSK'254 co‐administration. All 90% confidence intervals around geometric least‐squares mean ratios for cocktail substrate PK parameters indicated no to weak interactions. Steady‐state plasma GSK'254 concentrations were achieved by Day 17 and maintained through Day 21. Nine participants (45%) reported 17 AEs; most (88%) were grade 1. Two grade 2 treatment‐related AEs (maculopapular rash [leading to withdrawal] and papular rash) were reported during GSK'254 administration alone. Conclusions Co‐administration of GSK'254 with a metabolic probe cocktail in healthy participants indicated very low risk of clinically relevant effect on PK of any substrates or associated metabolites. No new safety/tolerability concerns were identified. These results support ongoing phase IIb and planned phase III studies of GSK'254 in people living with HIV‐1.

Effects of the HIV‐1 maturation inhibitor GSK3640254 on QT interval in healthy participants

“…This model predicted that the GSK'254 plasma concentration below which the upper bound of the 90% CI would remain <10 ms was 3070 ng mL −1 . This concentration is above the geometric mean C max observed with GSK'254 200 mg QD in previous studies of healthy participants (1040–1780 ng mL −1 ) 1,3,5–7,9,10 and treatment‐naive people living with HIV‐1 (1860 ng mL −1 ) 8 . As GSK'254 200 mg is the highest dose being evaluated in phase IIa and IIb studies of people living with HIV‐1, 8,11,12 the predicted mean C max for the 200 mg dose would not be associated with QT prolongation.…”

“…Previous phase I clinical studies of GSK'254 have demonstrated pharmacokinetics (PK) supportive of once‐daily (QD) therapy and a desirable drug–drug interaction profile, with no relevant interactions with common antiretroviral agents, including dolutegravir and tenofovir alafenamide/emtricitabine, or common drug‐metabolizing enzymes (such as cytochrome P450 enzymes and organic anion transporting polypeptide transporters) 3,5–7 . Under short‐term administration, GSK'254 was generally well tolerated in healthy participants and people living with HIV‐1 1–3,5,6,8 .…”

Pharmacokinetics and tolerability of the maturation inhibitor GSK3640254 coadministered with darunavir/ritonavir and/or etravirine in healthy adults

“…Whether higher doses of GSK'254 could alternatively mitigate the effect of ETR, such as may be done with maraviroc, 27 was not examined. Safety and tolerability were generally favourable after daily oral dosing with GSK'254320 mg for 2 weeks or 500 mg for 7 days in healthy participants, 17,45 but the PK and safety of GSK'254 after repeated administration of higher doses would require further investigation. Altogether, these data suggest that GSK'254 200 mg QD can be administered with ETR 200 mg BID and DRV/RTV 600/100 mg BID in the presence of a moderate‐fat meal with minimal effects on the plasma concentration of GSK'254.…”

“…24 Hepatobiliary secretion in the form of metabolites is a major elimination pathway of GSK'254. GSK'254 is primarily metabolized by cytochrome P450 3A4 (CYP3A4), CYP2C9, CYP1A2 and CYP2C8, 25 although CYP3A4 was identified as the only CYP enzyme that metabolized GSK'254 in human liver microsomes. 24 GSK'254 does not meaningfully induce or inhibit CYP enzymes (e.g., CYP1A2, CYP2D6, CYP2C8, CYP2C9, CYP2C19, CYP3A4) or transporters (e.g., P-glycoprotein, organic anion transporting polypeptide 1B1/3) 25 nor is it a substrate of those transporters.…”