Pharmacokinetics, pharmacodynamics and adverse event profile of GSK2256294, a novel soluble epoxide hydrolase inhibitor

Abstract

AIMSEndothelial-derived epoxyeicosatrienoic acids may regulate vascular tone and are metabolized by soluble epoxide hydrolase enzymes (sEH). GSK2256294 is a potent and selective sEH inhibitor that was tested in two phase I studies. METHODSSingle escalating doses of GSK2256294 2-20 mg or placebo were administered in a randomized crossover design to healthy male subjects or obese smokers. Once daily doses of 6 or 18 mg or placebo were administered for 14 days to obese smokers. Data were collected on safety, pharmacokinetics, sEH enzyme inhibition and blood biomarkers. Single doses of GSK2256294 10 mg were also administered to healthy younger males or healthy elderly males and females with and without food. Data on safety, pharmacokinetics and biliary metabolites were collected. RESULTSGSK2256294 was well-tolerated with no serious adverse events (AEs) attributable to the drug. The most frequent AEs were headache and contact dermatitis. Plasma concentrations of GSK2256294 increased with single doses, with a half-life averaging 25-43 h. There was no significant effect of age, food or gender on pharmacokinetic parameters. Inhibition of sEH enzyme activity was dose-dependent, from an average of 41.9% on 2 mg (95% confidence interval [CI] -51.8, 77.7) to 99.8% on 20 mg (95% CI 99.3, 100.0) and sustained for up to 24 h. There were no significant changes in serum VEGF or plasma fibrinogen.

Characterization of the Cytochrome P450 epoxyeicosanoid pathway in non-alcoholic steatohepatitis

“…The anti-inflammatory and cardiovascular protective effects of EETs are well-established (4–6, 49). Importantly, sEH inhibitors are in preclinical and clinical development for chronic inflammatory conditions (50, 51). Given the metabolic and hepatic protective effects in preclinical models of obesity and NAFLD/NASH described herein, promoting the effects of EETs has enormous potential as a novel therapeutic strategy for NAFLD/NASH and warrants further investigation.…”

Epoxyeicosatrienoic acids and glucose homeostasis in mice and men

“…[42] The tmax is 0.5 hours and t 1/2 is 48 hours. In multiple dosing studies in overweight smokers, steady-state was achieved within seven days.…”

Epoxygenated Fatty Acids Inhibit Retinal Vascular Inflammation

“…Accordingly, sEH represents a rational and promising therapeutic target. Thus, its inhibition has been the objective of multiple clinical trials in diabetes-related pathology3233343536. More specifically, these clinical trials have been directed at the treatment of hypertension and glucose tolerance in pre-diabetic patients, and pulmonary disease in obese male smokers3334.…”