Venglustat is a small-molecule glucosylceramide synthase (GCS) inhibitor designed to reduce the production of glucosylceramide (GL-1) and thus is expected to substantially reduce formation of glucosylceramide-based glycosphingolipids. Because of its effect on glycosphingolipid formation, GCS inhibition has therapeutic potential across many disorders affecting glycosphingolipid metabolism. Therefore, venglustat is under development for substrate reduction therapy in multiple diseases, including Gaucher disease type 3, Parkinson's disease associated with GBA mutations, Fabry disease, GM2 gangliosidosis, and autosomal dominant polycystic kidney disease. Phase 1 studies were conducted in healthy volunteers to determine venglustat pharmacokinetics, pharmacodynamics, safety, and tolerability and to assess food effects on pharmacokinetics (single-dose and food-effect studies: NCT01674036; repeated-dose study: NCT01710826). Following a single oral dose of venglustat L-malate (2, 5, 15, 25, 50, 100, or 150 mg), venglustat demonstrated linear pharmacokinetics, rapid absorption (median t max , 3.00-5.50 hours), systemic exposure unaffected by food, low apparent total body clearance (mean CL/F, 5.18-6.43 L/h), and pooled geometric mean t 1/2z of 28.9 hours. Following repeated once-daily oral doses of venglustat L-malate (5, 10, or 20 mg) for 14 days, apparent steady state occurred within 5 days of repeated dosing, with pooled accumulation ratios of 2.10 for C max and 2.22 for AUC 0-24 , and no statistically significant effect of dose or sex on accumulation. The mean fraction of dose excreted unchanged in urine (fe 0-24) was 26.3% to 33.1%. Plasma GL-1 and GM3 decreased time-and dose-dependently. Venglustat demonstrated a favorable safety and tolerability profile.

range of HIV polymorphisms with no cross-resistance to current antiretroviral therapy, could potentially be coadministered with dolutegravir as a 2-drug regimen. In this phase I study, pharmacokinetics and tolerability of GSK3640254 plus dolutegravir were assessed. Methods: Healthy participants received dolutegravir 50 mg once daily (QD) on Days 1-5 in period 1, GSK3640254 200 mg QD on Days 1-7 in period 2, and dolutegravir 50 mg plus GSK3640254 200 mg QD on Days 1-7 in period 3. All treatments were administered with a moderate-fat meal 30 minutes prior to dosing. Pharmacokinetics parameters were derived by noncompartmental methods, and geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were derived using linear mixed effects models. Adverse events, laboratory measurements, electrocardiography and vital signs were monitored. Results: Sixteen participants completed the study. GMRs (90% CIs) for dolutegravir area under the plasma concentration-time curve from time 0 to the end of the dosing interval at steady state, maximum observed concentration and plasma concentration at the end of the dosing interval were 1.17 (1.118-1.233), 1.09 (1.044-1.138) and 1.24 (1.160-1.315), respectively. The GMRs (90% CIs) for GSK3640254 were 1.04

Aims: GSK3640254 is a next-generation maturation inhibitor likely to be coadministered with combined oral contraceptives in HIV-positive women.Methods: This phase I, open-label, 1-way study assessed pharmacokinetic and pharmacodynamic interactions of GSK3640254 200 mg and ethinyl oestradiol 0.03 mg/ levonorgestrel 0.15 mg once daily in healthy female participants who received ethinyl oestradiol/levonorgestrel for 10 days with a moderate-fat meal after which GSK3640254 was added from Days 11 to 21. Primary endpoints were area under the plasma concentration-time curve to the end of the dosing interval (AUC 0-t ), maximum observed concentration (C max ) and plasma concentration at the end of the dosing interval (C τ ) for ethinyl oestradiol and levonorgestrel. Serum follicle-stimulating hormone, luteinizing hormone and progesterone concentrations were determined.Adverse events were monitored.Results: Among 23 enrolled participants, 17 completed the study. Geometric least squares mean ratios (with vs. without GSK3640254) of AUC 0-t , C max and C τ were 0.974, 0.970 and 1.050 for ethinyl oestradiol and 1.069, 1.032 and 1.083 for levonorgestrel, respectively. Three participants had elevated progesterone levels, which occurred before GSK3640254 administration in 2 participants. No participants had elevated follicle-stimulating hormone or luteinizing hormone values. Fourteen participants (61%) reported adverse events. Four participants reported asymptomatic elevated transaminase levels meeting liver-stopping criteria; of these, 3 events occurred before GSK3640254 administration and led to study withdrawal. Conclusion:Ethinyl oestradiol/levonorgestrel plus GSK3640254 coadministration did not affect steady-state pharmacokinetics or pharmacodynamics of ethinyl oestradiol Employee of GlaxoSmithKline Teodora Pene Dumitrescu, Jianfeng Xu or PPD Theresa T. Pham at the time of the study.The authors confirm that the Principal Investigator for this paper is Theresa T. Pham and that she had direct clinical responsibility for participants.

Three times daily dosing of 0.5 mg oral treprostinil for 7 days was well tolerated in healthy subjects and provided sustained plasma exposure throughout the day at steady state without drug accumulation. This study provides data to support further evaluation of TID dosing regimen of oral treprostinil.

This study aimed to determine the impact of food on the pharmacokinetics of orteronel, an investigational nonsteroidal, reversible selective inhibitor of 17,20-lyase. In this open-label, randomized crossover study, healthy subjects received single doses of orteronel 400 mg with a low-fat meal, a high-fat meal, and under fasting conditions in a randomized sequence. Plasma concentrations of orteronel and its primary M-I metabolite were determined by ultra-performance liquid chromatography, and pharmacokinetic parameters were evaluated using mixed-effects analysis of variance model. Compared with fasting conditions, the oral bioavailability of orteronel was increased under fed conditions. The least-squares mean ratio for area under the plasma concentration-time curve after a low-fat breakfast was 135% (90% confidence interval [CI], 126%-145%) compared with fasting conditions. Similarly, after a high-fat breakfast, the corresponding value was 142% (90%CI, 132%-152%). No unexpected safety concerns were raised with orteronel 400 mg administered in the fasted state or after either a high-fat or a low-fat meal; mild adverse events were experienced by 36% of the healthy male subjects.