Pharmacokinetics and pharmacodynamics of AR9281, an inhibitor of soluble epoxide hydrolase, in single- and multiple-dose studies in healthy human subjects

• Published in: Journal of clinical pharmacology Vol. 52; no. 3; p. 319
• Main Authors: Chen, Dawn, Whitcomb, Randall, MacIntyre, Euan, Tran, Vinh, Do, Zung N, Sabry, James, Patel, Dinesh V, Anandan, Sampath K, Gless, Richard, Webb, Heather K
• Format: Journal Article
• Language: English
• Published: England 01.03.2012
• Subjects: Adamantane - adverse effects; Adamantane - analogs & derivatives; Adamantane - blood; Adamantane - pharmacokinetics; Adult; Area Under Curve; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Epoxide Hydrolases - antagonists & inhibitors; Female; Half-Life; Humans; Male; Middle Aged; Urea - adverse effects; Urea - analogs & derivatives; Urea - blood; Urea - pharmacokinetics; Young Adult
• ISSN: 1552-4604
• DOI: 10.1177/0091270010397049

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.