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.

New Approaches in the Treatment of Hypertension

“…Randomized double-blind, placebo-controlled studies in healthy volunteers have shown that AR9281 dose-dependently inhibits s-EH at doses that are well tolerated. 103 A randomized double-blind, placebo-controlled dose-ranging phase II study in patients with mild to moderate hypertension and impaired glucose tolerance was terminated in November 2009, and no efficacy results have been reported, suggesting that it was ineffective in lowering BP 104 (ClinicalTrials.gov: NCT00847899). However, s-EH inhibitors have other promising therapeutic applications, for example, inflammation, pain, and CVD that warrant future investigation.…”

Role of Cytochrome P450s in Inflammation

“…There is potential therapeutic value of increasing EET activity for inflammatory and cardiovascular disease, metabolic syndrome, tissue regeneration, and pain management. sEH inhibitors have already been tested in human subjects and are undergoing continued development (Chen, Whitcomb, et al, 2012;Imig & Hammock, 2009). It is unlikely that the global reduction of EET metabolism by sEH inhibition will be without side effects, and there is concern that increasing EET levels will promote cancer (Panigrahy et al, 2011).…”

Reno-protective mechanisms of epoxyeicosatrienoic acids in cardiovascular disease

“…As shown in Fig. 1, the CYP monooxygense pathway catalyzes the oxidation of arachidonic acid at any of the four double bonds to four regioisomeric epoxyeicosatrienoic acids (EETs) (5,8,11,and 14, by the CYP epoxygenase and/or 19-and 20-hydroxyl eicosatetraenoic acids by the CYP -hydroylase (34,47,95,106). EETs and 20-HETE have been identified as the main metabolic products of arachidonic acid in rodent and human tissues (47,117).…”

“…Inhibition of sEH also reduced the elevation of blood pressure in high-fat diet-fed rats and mice and other experimental models of metabolic syndrome (43,104). Clinically, the sEH inhibitor AR9281 has recently completed a phase IIA clinical trial in patients with mild to moderate hypertension and impaired glucose tolerance (14).…”

“…The right kidney was subject to ischemia for 45 min followed by reperfusion for 4 h. Percentage of renal apoptotic/necrotic cells was elevated in right, compared with left, kidney, and inhibition of sEH with AUCB treatment reduced this percentage in both kidneys (n ϭ 3 per group). IIA clinical trial in hypertensive patients with impaired glucose tolerance (14). Because the inhibition of sEH has been shown to reduce COX-2 expression (97), sEH inhibitors could be used in combination with traditional nonsteroidal anti-inflammatory drugs or selective COX-2 inhibitors to synergize their antiinflammatory properties in CVD and reduced their cardiotoxic side effects.…”