PHASE 1, DOSE-RANGING STUDY OF EMIXUSTAT HYDROCHLORIDE (ACU-4429), A NOVEL VISUAL CYCLE MODULATOR, IN HEALTHY VOLUNTEERS
PHASE 1, DOSE-RANGING STUDY OF EMIXUSTAT HYDROCHLORIDE (ACU-4429), A NOVEL VISUAL CYCLE MODULATOR, IN HEALTHY VOLUNTEERS
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DOI：
10.1097/01.iae.0000434565.80060.f8
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发表时间：
2014-03-01
影响因子：
3.3
通讯作者：
Chandler, John W.
中科院分区：
文献类型：
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作者：
Kubota, Ryo;Al-Fayoumi, Suliman;Chandler, John W.
背景资料：盐酸Emixustat（以前称为ACU-4429）是一种非类维生素A化合物，在视网膜色素上皮中具有独特的作用模式，通过对视网膜色素上皮特异性65 kDa蛋白异构酶的作用调节视觉发色团的生物合成。本研究为临床医生了解口服emixustat.Methods的药代动力学和安全性提供了背景：本随机、双盲、安慰剂对照的1b期研究评价了14天口服emixustat的药代动力学、耐受性和安全性（5、10、20、30或40 mg）或安慰剂（3：1比例）每日一次在健康志愿者中进行。Emixustat（n = 30）吸收迅速（中位Tmax，3.0-5小时）且易于消除（平均t（1/2），4.6-7.9小时），平均C-max和AUC（0-24）通常与剂量成比例增加。多次给药后，未观察到emixustat的显着蓄积。接受emixustat的受试者中有67%发生了眼部不良事件;所有事件均被认为是轻度的，并在研究完成后消退。全身不良事件是minimal.Conclusion：口服emixustat是安全的，耐受性良好，每天给药一次，持续14天，报告的全身不良事件最少。这些数据支持emixustat在与干性年龄相关性黄斑变性相关的地图状萎缩受试者中的评价。
Background: Emixustat hydrochloride (formerly ACU-4429) is a nonretinoid compound with a unique mode of action in the retinal pigment epithelium, where it modulates the biosynthesis of visual chromophore through its effect on retinal pigment epithelium-specific 65 kDa protein isomerase. This study provides clinicians with a background for understanding the pharmacokinetics and safety profile of orally administered emixustat.Methods: This randomized, double-masked, placebo-controlled Phase 1b study evaluated the pharmacokinetics, tolerability, and safety of a 14-day course of oral emixustat (5, 10, 20, 30, or 40 mg) or placebo (3: 1 ratio) once daily in healthy volunteers.Results: A total of 40 subjects were enrolled (mean age, 38 years; 75% male). Emixustat (n = 30) was rapidly absorbed (median T-max, 3.0-5 hours) and readily eliminated (mean t(1/2), 4.6-7.9 hours), and mean C-max and AUC(0-24) generally increased in proportion to dose. No significant accumulation of emixustat was observed with multiple-dose administration. Ocular adverse events occurred in 67% of the subjects who received emixustat; all were considered mild and resolved after study completion. Systemic adverse events were minimal.Conclusion: Oral emixustat was safe and well tolerated when administered once daily for 14 days with minimal systemic adverse events reported. These data support evaluation of emixustat in subjects with geographic atrophy associated with dry age-related macular degeneration.