Pharmacokinetics and Pharmacodynamics of AR9281, an Inhibitor of Soluble Epoxide Hydrolase, in Single- and Multiple-Dose Studies in Healthy Human Subjects
Pharmacokinetics and Pharmacodynamics of AR9281, an Inhibitor of Soluble Epoxide Hydrolase, in Single- and Multiple-Dose Studies in Healthy Human Subjects
复制标题
DOI：
10.1177/0091270010397049
复制
发表时间：
2012-03-01
影响因子：
2.9
通讯作者：
Webb, Heather K.
中科院分区：
文献类型：
--
作者：
Chen, Dawn;Whitcomb, Randall;Webb, Heather K.
AR9281是一种有效的、选择性的可溶性环氧化物水解酶（s - EH）抑制剂，正处于针对高血压和2型糖尿病的临床开发阶段。在健康受试者中进行了双盲、随机、安慰剂对照、剂量递增的单次口服剂量（10 - 1000毫克）和多次剂量（100 - 400毫克，每8小时一次，持续7天）研究，对AR9281的安全性、药代动力学和药效学进行了评估。AR9281耐受性良好，在两项研究中均未观察到剂量相关的不良事件。该药物吸收迅速，平均终末半衰期为3到5小时。血浆浓度 - 时间曲线下面积在500毫克剂量以内大致呈剂量比例增加，在更高剂量时呈现出大于剂量线性的关系。AR9281直接且剂量依赖性地抑制血液中s - EH活性，在250毫克剂量时8小时内以及500毫克剂量时12小时内抑制率达到90%或更高。每8小时给予100 - 400毫克的多次剂量AR9281，在谷浓度时可使s - EH活性持续抑制在90%或更高水平。目前的研究证明了AR9281在健康受试者中的安全性以及对靶点的抑制作用。AR9281的药代动力学和药效学特征支持在患者中采用每日两次或每日三次的给药方案。
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.