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

Abstract

AimsThis phase I study investigated potential drug–drug interactions of the maturation inhibitor GSK3640254 (GSK'254) with darunavir/ritonavir (DRV/RTV) and/or etravirine (ETR).MethodsIn this randomized, open‐label, single‐sequence, multiple‐dose study, healthy participants received GSK'254 200 mg once daily alone or coadministered with DRV/RTV 600/100 mg twice daily (BID; n = 19), ETR 200 mg BID (n = 19) or DRV/RTV 600/100 mg + ETR 200 mg BID (n = 16) under fed conditions. Primary endpoints were steady‐state area under the plasma concentration–time curve from time 0 to the end of the dosing interval (AUC0‐τ) and maximum observed concentration (Cmax). Secondary endpoints included trough concentration (Cτ), safety and tolerability. Pharmacokinetic parameters were calculated using standard noncompartmental analysis, and geometric least‐squares mean ratios were derived from linear mixed‐effects models.ResultsGSK'254 AUC0‐τ (geometric least‐squares mean ratio [90% confidence interval], 1.14 [1.00–1.29]), Cmax (1.07 [0.92–1.24]) and Cτ (1.17 [1.01–1.35]) were similar when administered alone and with DRV/RTV. Etravirine coadministration decreased GSK'254 AUC0‐τ (0.53 [0.48–0.59]), Cmax (0.60 [0.53–0.68]) and Cτ (0.51 [0.39–0.66]). Similar reductions were not observed with GSK'254 + DRV/RTV + ETR (AUC0‐τ, 0.94 [0.82–1.09]; Cmax, 0.89 [0.75–1.07]; Cτ, 1.02 [0.89–1.18]). GSK'254 had no meaningful effect on DRV/RTV or ETR concentrations. All reported adverse events (AEs) were grade 1; 3 led to withdrawal and resolved (rash, asymptomatic electrocardiogram T‐wave inversion, periorbital oedema). Most common AEs were diarrhoea (n = 9) and headache (n = 7). No deaths or serious AEs occurred.ConclusionGSK'254 pharmacokinetics was not meaningfully affected by DRV/RTV or DRV/RTV + ETR, but were reduced with only ETR; no new tolerability concerns were observed.