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Aims: This phase I study investigated potential drug-drug interactions of the maturation inhibitor GSK3640254 (GSK'254) with darunavir/ritonavir (DRV/RTV) and/or etravirine (ETR).
Methods: In 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 (AUC ) and maximum observed concentration (C ). Secondary endpoints included trough concentration (C ), safety and tolerability. Pharmacokinetic parameters were calculated using standard noncompartmental analysis, and geometric least-squares mean ratios were derived from linear mixed-effects models.
Results: GSK'254 AUC (geometric least-squares mean ratio [90% confidence interval], 1.14 [1.00-1.29]), C (1.07 [0.92-1.24]) and C (1.17 [1.01-1.35]) were similar when administered alone and with DRV/RTV. Etravirine coadministration decreased GSK'254 AUC (0.53 [0.48-0.59]), C (0.60 [0.53-0.68]) and C (0.51 [0.39-0.66]). Similar reductions were not observed with GSK'254 + DRV/RTV + ETR (AUC , 0.94 [0.82-1.09]; C , 0.89 [0.75-1.07]; C , 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.
Conclusion: GSK'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.
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