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

Aili L. Lazaar*, Lucy Yang, Rebecca L. Boardley, Navin S. Goyal, Jonathan Robertson, Sandra J. Baldwin, David E. Newby, Ian B. Wilkinson, Ruth Tal-Singer, Ruth J. Mayer, Joseph Cheriyan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

91 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)971-979
Number of pages9
JournalBritish Journal of Clinical Pharmacology
Issue number5
Publication statusPublished - 1 May 2016
Externally publishedYes


  • clinical pharmacology
  • clinical trial
  • COPD
  • smoking
  • soluble epoxide hydrolase


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