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Pharmacokinetics and Pharmacodynamics of AR9281, an Inhibitor of Soluble Epoxide Hydrolase, in Single‐ and Multiple‐Dose Studies in Healthy Human Subjects
Author(s) -
Chen Dawn,
Whitcomb Randall,
MacIntyre Euan,
Tran Vinh,
Do Zung N.,
Sabry James,
Patel Dinesh V.,
Anandan Sampath K.,
Gless Richard,
Webb Heather K.
Publication year - 2012
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270010397049
Subject(s) - pharmacokinetics , pharmacodynamics , pharmacology , medicine , adverse effect , dose–response relationship , dosing , placebo , alternative medicine , pathology
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.