Aim: Fostemsavir (FTR), an extended-release prodrug of temsavir (TMR), is a human immunodeficiency virus type 1 (HIV-1) attachment inhibitor approved for the treatment of multidrug-resistant HIV-1 infection in heavily treatment-experienced (HTE) patients failing current antiretroviral treatment. A population PK and exposure-response analysis was performed to assess the influence of intrinsic/extrinsic factors and support regulatory approval of 600 mg BID fostemsavir regimen. Methods: Analysis was conducted using TMR data from seven clinical studies (Phases 1-3). Models were assessed using standard goodness of fit and parameter precision (root mean square error (%RSE)). Model-estimated exposure metrics were used to assess TMR PK- efficacy and safety exposure response relationships. Results: TMR PK was adequately described using a two-compartment model with zero and first-order absorption and first-order elimination. Clearance, volume and absorption parameters were precisely estimated (CL/F 51.0 L/hr (2.1% RSE), V2/F 257 1/hr (3.18 %RSE), Ka 2.33 1/hr (13.3 %RSE)). Concomitant CYP3A inducers and inhibitors were covariates on CL/F, and body weight was a covariate on CL/F, V2/F, Q/F, and V3/F. An Emax model described the trough TMR concentration (Ctau) - day 8 plasma HIV-1 RNA relationship (Emax 1.00 log10 c/mL (17.1 %RSE), EC50 64.3 ng/mL (98% RSE)). No exposure-safety relationships were evident. Simulation showed virologic response was achieved irrespective of coadministration with moderate CYP3A inducers, strong CYP3A inhibitors, changes in prandial status, or body weight. Conclusion: Results support administration of FTR 600 mg BID to decrease virologic load in HIV-1 HTE patients, with no dose adjustments necessary for intrinsic or extrinsic factors.

Aim: Prostaglandin D2 (PGD2) is implicated in the pathophysiology of inflammatory diseases. GSK3439171A is a potent, reversible, and highly selective azetidine urea inhibitor of haematopoietic prostaglandin D synthase (H-PGDS, a key promoter of PGD2 production in several inflammatory cell types). Based on favourable preclinical data, we performed a first-time-in-human study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of GSK3439171A, and the effect of food on these parameters. Methods: This was a phase 1, randomized, double-blind, placebo-controlled, dose-escalation study. Single and repeat oral doses of GSK3439171A were administered to healthy males aged 18–65 years. Levels of inflammatory markers including tetranor-prostaglandin D metabolite (tPGDM) were measured in urine samples. Results: Sixty-six participants were enrolled, with 57 receiving GSK3439171A. Single doses (5–180 mg) and repeat once-daily doses (5 and 11 mg for 14 days; 40 mg for 7 days) were administered. Seven participants (12%) had adverse events (AEs) related to study drug, mainly drug hypersensitivity (n=4 [7%]; non-serious, transient skin rash). There were no serious AEs (SAEs) or clinically significant changes in vital signs, electrocardiogram, or laboratory parameters. Dose-proportional increases in Cmax and AUC(0–inf) were observed, and the geometric mean half-life of GSK3439171A was up to 12 hours. Results were similar when GSK3439171A was taken with or without food. No consistent suppression of tPGDM levels was observed. Conclusion: GSK3439171A was well tolerated in healthy participants and there were no SAEs. Selective inhibition of H-PGDS offers therapeutic potential for muscle-related disorders (e.g. Duchenne Muscular Dystrophy) and muscular recovery following injury.