title: Pharmacokinetics and pharmacodynamics of AR9281, an inhibitor of soluble epoxide hydrolase, in single- and multiple-dose studies in healthy human subjects.
abstract: AR9281, a potent and selective inhibitor of soluble epoxide hydrolase (s-EH), is in clinical development targeting hypertension and type 2 diabetes. The safety, pharmacokinetics, and pharmacodynamics of AR9281 were evaluated in double-blind, randomized, placebo-controlled, ascending, single oral dose (10-1000 mg) and multiple dose (100-400 mg every 8 hours for 7 days) studies in healthy subjects. AR9281 was well tolerated, and no dose-related adverse events were observed during either study. The drug was rapidly absorbed with a mean terminal half-life ranging from 3 to 5 hours. The area under the plasma concentration-time curve increased in an approximately dose-proportional manner up to the 500-mg dose and exhibited a greater than dose linearity at higher doses. AR9281 directly and dose-dependently inhibited blood s-EH activity with 90% inhibition or greater over an 8-hour period at the 250-mg dose and over a 12-hour period at the 500-mg dose. Multiple doses of AR9281 ranging from 100 to 400 mg every 8 hours resulted in a sustained inhibition of s-EH activity at 90% or greater during the trough. The current studies provide proof of safety and target inhibition of AR9281 in healthy subjects. AR9281 pharmacokinetic and pharmacodynamic characteristics support a twice-daily or thrice-daily dosing regimen in patients.
authors.affiliation: Arete Therapeutics, Inc, 7000 Shoreline Court, South San Francisco, CA 94080, USA. dawnchen96@yahoo.com
authors.forename: Dawn
authors.initials: D
authors.lastname: Chen
authors.forename: Randall
authors.initials: R
authors.lastname: Whitcomb
authors.forename: Euan
authors.initials: E
authors.lastname: MacIntyre
authors.forename: Vinh
authors.initials: V
authors.lastname: Tran
authors.forename: Zung N
authors.initials: ZN
authors.lastname: Do
authors.forename: James
authors.initials: J
authors.lastname: Sabry
authors.forename: Dinesh V
authors.initials: DV
authors.lastname: Patel
authors.forename: Sampath K
authors.initials: SK
authors.lastname: Anandan
authors.forename: Richard
authors.initials: R
authors.lastname: Gless
authors.forename: Heather K
authors.initials: HK
authors.lastname: Webb
mesh_terms: D000218:Adamantane / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D014508:Urea / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: C557705:1-(1-acetyl-piperidine-4-yl)-3-adamantan-1-yl-urea; D014508:Urea; D004851:Epoxide Hydrolases; D000218:Adamantane