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

Autor: Lazaar AL; GSK R&D, King of Prussia, Pennsylvania, USA., Yang L; Experimental Medicine & Immunotherapeutics, Department of Medicine, University of Cambridge, and Cambridge Clinical Trials Unit, Cambridge., Boardley RL; GSK R&D, Stevenage, Cambridge and Ware., Goyal NS; GSK R&D, King of Prussia, Pennsylvania, USA., Robertson J; GSK R&D, Stevenage, Cambridge and Ware., Baldwin SJ; GSK R&D, Stevenage, Cambridge and Ware., Newby DE; University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK., Wilkinson IB; Experimental Medicine & Immunotherapeutics, Department of Medicine, University of Cambridge, and Cambridge Clinical Trials Unit, Cambridge., Tal-Singer R; GSK R&D, King of Prussia, Pennsylvania, USA., Mayer RJ; GSK R&D, King of Prussia, Pennsylvania, USA., Cheriyan J; Experimental Medicine & Immunotherapeutics, Department of Medicine, University of Cambridge, and Cambridge Clinical Trials Unit, Cambridge.; GSK R&D, Stevenage, Cambridge and Ware.; Cambridge University Hospitals NHS Foundation Trust, Cambridge and.
Jazyk: angličtina
Zdroj: British journal of clinical pharmacology [Br J Clin Pharmacol] 2016 May; Vol. 81 (5), pp. 971-9. Date of Electronic Publication: 2016 Jan 17.
DOI: 10.1111/bcp.12855
Abstrakt: Aims: Endothelial-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.
Methods: Single 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.
Results: GSK2256294 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.
Conclusions: GSK2256294 was well-tolerated and demonstrated sustained inhibition of sEH enzyme activity. These data support further investigation in patients with endothelial dysfunction or abnormal tissue repair, such as diabetes, wound healing or COPD.
(© 2015 The British Pharmacological Society.)
Databáze: MEDLINE
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