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Chronic pain represents a significant unmet medical need, affecting one‐fifth of the U.S. population. EC5026 is a small molecule inhibitor of the enzyme soluble epoxide hydrolase (sEH) which is being developed as a novel non‐opioid, non‐NSAID analgesic. EC5026 prolongs the action of epoxy fatty acids, endogenous analgesic lipid mediators that are rapidly metabolized by sEH. We evaluated the safety and pharmacokinetic profile of EC5026 in two phase I trials, a single‐ascending dose (SAD) study and a fed‐fasted study. The SAD study evaluated EC5026 doses ranging from 0.5 to 24 mg in healthy volunteers. EC5026 was well tolerated. No treatment‐emergent adverse events were considered related to EC5026. No apparent treatment‐ or dose‐related trends in laboratory results, vital signs, physical examinations, or electrocardiograms were observed. A linear, near‐dose‐proportional increase in exposure was observed with progressive doses in the SAD study; plasma exposure was below or near the lower limit of quantification after 0.5–2 mg doses. Mean half‐lives ranged from 41.8 to 59.1 h. for doses of 8–24 mg, supporting a once‐daily dosing regimen. In the fed‐fasted study using 8 mg EC5026 tablets, higher peak concentrations (66%) and total exposures (53%) were observed under the fed condition. Plasma concentrations declined in a monoexponential manner with mean half‐lives of 59.5 h. in the fed state and 66.9 h. in the fasted state. Future clinical trials using EC5026 for the treatment of pain are justified based on the favorable outcomes from both clinical trials along with preclinical evidence of analgesic activity. [ABSTRACT FROM AUTHOR]

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 (AUC0‐t), maximum observed concentration (Cmax) and plasma concentration at the end of the dosing interval (Cτ) 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 AUC0‐t, Cmax and Cτ 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 and levonorgestrel in healthy female participants. No major tolerability findings were reported. Elevated liver transaminase levels were probably due to ethinyl oestradiol/levonorgestrel. [ABSTRACT FROM AUTHOR]

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 tmax, 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 t1/2z 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 Cmax and 2.22 for AUC0–24, and no statistically significant effect of dose or sex on accumulation. The mean fraction of dose excreted unchanged in urine (fe0–24) was 26.3% to 33.1%. Plasma GL‐1 and GM3 decreased time‐ and dose‐dependently. Venglustat demonstrated a favorable safety and tolerability profile. [ABSTRACT FROM AUTHOR]

Chronic pain represents a significant unmet medical need, affecting one-fifth of the U.S. population. EC5026 is a small molecule inhibitor of the enzyme soluble epoxide hydrolase (sEH) which is being developed as a novel non-opioid, non-NSAID analgesic. EC5026 prolongs the action of epoxy fatty acids, endogenous analgesic lipid mediators that are rapidly metabolized by sEH. We evaluated the safety and pharmacokinetic profile of EC5026 in two phase I trials, a single-ascending dose (SAD) study and a fed-fasted study. The SAD study evaluated EC5026 doses ranging from 0.5 to 24 mg in healthy volunteers. EC5026 was well tolerated. No treatment-emergent adverse events were considered related to EC5026. No apparent treatment- or dose-related trends in laboratory results, vital signs, physical examinations, or electrocardiograms were observed. A linear, near-dose-proportional increase in exposure was observed with progressive doses in the SAD study; plasma exposure was below or near the lower limit of quantification after 0.5-2 mg doses. Mean half-lives ranged from 41.8 to 59.1 h. for doses of 8-24 mg, supporting a once-daily dosing regimen. In the fed-fasted study using 8 mg EC5026 tablets, higher peak concentrations (66%) and total exposures (53%) were observed under the fed condition. Plasma concentrations declined in a monoexponential manner with mean half-lives of 59.5 h. in the fed state and 66.9 h. in the fasted state. Future clinical trials using EC5026 for the treatment of pain are justified based on the favorable outcomes from both clinical trials along with preclinical evidence of analgesic activity., (© 2024 EicOsis Human Health, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)