Pharmacokinetics and Tolerability of the Maturation Inhibitor GSK3640254 Co-Administered With Darunavir/Ritonavir and/or Etravirine in Healthy Adults.

AIM: 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 co-administered 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 non-compartmental analysis, and geometric least-squares mean ratios (GMRs) were derived from linear mixed-effects models. RESULTS: GSK'254 AUC0-τ (GMR [90% CI], 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 co-administration 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; three led to withdrawal and resolved (rash, asymptomatic electrocardiogram T-wave inversion, periorbital edema). Most common AEs were diarrhea (n=9) and headache (n=7). No deaths or serious AEs occurred. CONCLUSION: GSK'254 pharmacokinetics were not meaningfully affected by DRV/RTV or DRV/RTV + ETR, but were reduced with only ETR; no new tolerability concerns were observed.