title: Pharmacokinetics, pharmacodynamics and adverse event profile of GSK2256294, a novel soluble epoxide hydrolase inhibitor.
abstract: OBJECTIVE
  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.
authors.affiliation: GSK R&D, King of Prussia, Pennsylvania, USA.
authors.forename: Aili L
authors.initials: AL
authors.lastname: Lazaar
authors.affiliation: Experimental Medicine & Immunotherapeutics, Department of Medicine, University of Cambridge, and Cambridge Clinical Trials Unit, Cambridge.
authors.forename: Lucy
authors.initials: L
authors.lastname: Yang
authors.affiliation: GSK R&D, Stevenage, Cambridge and Ware.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Boardley
authors.affiliation: GSK R&D, King of Prussia, Pennsylvania, USA.
authors.forename: Navin S
authors.initials: NS
authors.lastname: Goyal
authors.affiliation: GSK R&D, Stevenage, Cambridge and Ware.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Robertson
authors.affiliation: GSK R&D, Stevenage, Cambridge and Ware.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Baldwin
authors.affiliation: University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: David E
authors.initials: DE
authors.lastname: Newby
authors.affiliation: Experimental Medicine & Immunotherapeutics, Department of Medicine, University of Cambridge, and Cambridge Clinical Trials Unit, Cambridge.
authors.forename: Ian B
authors.initials: IB
authors.lastname: Wilkinson
authors.affiliation: GSK R&D, King of Prussia, Pennsylvania, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Tal-Singer
authors.affiliation: GSK R&D, King of Prussia, Pennsylvania, USA.
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Mayer
authors.affiliation: 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.
authors.forename: Joseph
authors.initials: J
authors.lastname: Cheriyan
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D015331:Cohort Studies; D018592:Cross-Over Studies; D003514:Cyclohexylamines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D003877:Dermatitis, Contact / Q000209:etiology; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006207:Half-Life; D006261:Headache / Q000139:chemically induced; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000188:drug therapy*; D014227:Triazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D003514:Cyclohexylamines; D004791:Enzyme Inhibitors; C584201:N-((4-cyano-2-(trifluoromethyl)phenyl)methyl)-3-((4-methyl-6-(methylamino)-1,3,5-triazin-2-yl)amino)cyclohexanecarboxamide; D014227:Triazines; D004851:Epoxide Hydrolases; C506428:EPHX2 protein, human; D015126:8,11,14-Eicosatrienoic Acid
keywords: COPD; clinical pharmacology; clinical trial; smoking; soluble epoxide hydrolase