Clinical Safety, Pharmacokinetics, and Pharmacodynamics of the 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor ABT-384 in Healthy Volunteers and Elderly Adults
Clinical Safety, Pharmacokinetics, and Pharmacodynamics of the 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor ABT-384 in Healthy Volunteers and Elderly Adults
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DOI：
10.1002/cpdd.5
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发表时间：
2013-04-01
影响因子：
2
通讯作者：
Dutta, Sandeep
中科院分区：
文献类型：
--
作者：
Liu, Wei;Katz, David A.;Dutta, Sandeep
ABT-384是一种有效的选择性11 β -羟基类固醇脱氢酶1型（HSD-1）抑制剂，该酶在多种组织中再生皮质醇。ABT-384进行了两项临床研究，以评估其在健康受试者中的安全性、药代动力学、靶向性和药理作用。健康成人接受1至240毫克单次剂量和1至100毫克多次剂量，每日1次，连续7-14天。老年受试者接受10 - 100mg的多次剂量，每日一次，连续21天。共有103名受试者接受了至少1剂ABT-384。两项研究均未定义最大耐受剂量。ABT-384的药代动力学特征及其活性代谢物支持每日一次给药。尿液皮质醇代谢物分析显示，每天1毫克的方案完全抑制肝脏HSD-1，并证实了体外靶标选择性。药理学效应包括促肾上腺皮质激素水平、皮质醇分泌、雄激素和雌二醇水平的增加。ABT-384具有相对于完全肝靶标结合的广泛治疗指数，这与糖尿病和代谢综合征等适应症相关。其对阿尔茨海默病等其他潜在适应症的治疗指标仍有待确定。
ABT-384 is a potent and selective inhibitor of 11 beta-hydroxysteroid dehydrogenase type 1 (HSD-1), the enzyme that regenerates cortisol in several tissues. Two clinical studies of ABT-384 were undertaken to assess its safety, pharmacokinetics, target engagement, and pharmacologic effects in healthy subjects. Single doses from 1 to 240 mg, and multiple doses from 1 to 100 mg once daily for 7-14 days, were administered to healthy adults. Multiple doses from 10 to 100 mg once daily for 21 days were administered to elderly subjects. A total of 103 subjects received at least 1 dose of ABT-384. A maximum-tolerated dose was not defined in either study. The pharmacokinetic profiles of ABT-384 and its active metabolite support once daily dosing. Analysis of urine cortisol metabolites demonstrated full hepatic HSD-1 inhibition with regimens from 1 mg daily, and confirmed in vitro target selectivity. Pharmacologic effects included increases of adrenocorticotrophic hormone levels, cortisol production and androgen and estradiol levels. ABT-384 has a wide therapeutic index relative to full hepatic target engagement which is relevant for indications such as diabetes and metabolic syndrome. Its therapeutic index for other potential indications such as Alzheimer's disease remains to be established.