Astellas Pharma Global Development, Inc., One Astellas Way, Northbrook, IL, 60062, USA.
Clinilabs Drug Development Corporation, New York, USA.
Psychopharmacology (Berl). 2021 Mar;238(3):867-876. doi: 10.1007/s00213-020-05738-y. Epub 2021 Jan 12.
Previous research suggests that sleep polysomnography and EEG endpoints can be used to assess GABAergic activity; however, the impact of GABA receptor positive allosteric modulators on sleep endpoints remains unclear.
This phase 1 study compared a single dose of ASP8062 (35 mg or 70 mg), a GABA receptor positive allosteric modulator, with placebo and paroxetine (40 mg).
Healthy adult volunteers were randomized to four treatments (35 mg ASP8062, 70 mg ASP8062, paroxetine 40 mg, or matching placebo), each separated by a 14-day washout. Primary endpoints obtained by polysomnography were time in stage N3 or SWS and time in rapid eye movement (REM) sleep. Secondary endpoints included impact on sleep stages and electroencephalography parameters, pharmacokinetics, nighttime growth hormone (GH), and safety/tolerability.
In 20 randomized volunteers, ASP8062 led to a significant and seemingly dose-dependent increase in SWS over the entire night; this increase was mainly observed during the first third of the night. ASP8062 did not impact time in REM sleep. Paroxetine had no effect on SWS but produced a significant reduction in time spent in REM sleep. A dose-dependent trend in increased GH release was also observed with ASP8062. Headache and nausea were the most commonly reported treatment-emergent adverse events (TEAEs) for ASP8062; most TEAEs were mild in severity.
Single-dose ASP8062 (35 and 70 mg) appeared to result in CNS penetration and enhanced GABAergic activity as measured by increases in slow-wave sleep and growth hormone release.
先前的研究表明，睡眠多导图和脑电图终点可用于评估 GABA 能活性；然而，GABA 受体正变构调节剂对睡眠终点的影响仍不清楚。
这项 1 期研究比较了单剂量 ASP8062（35mg 或 70mg）、一种 GABA 受体正变构调节剂与安慰剂和帕罗西汀（40mg）的效果。
健康成年志愿者随机分为四组治疗（35mg ASP8062、70mg ASP8062、帕罗西汀 40mg 或匹配的安慰剂），每组间隔 14 天洗脱期。通过多导睡眠图获得的主要终点是 N3 期或慢波睡眠（SWS）时间和快速眼动（REM）睡眠时间。次要终点包括对睡眠阶段和脑电图参数、药代动力学、夜间生长激素（GH）的影响以及安全性/耐受性。
在 20 名随机志愿者中，ASP8062 导致 SWS 明显且似乎呈剂量依赖性增加，整夜均如此；这种增加主要发生在夜间的前三分之一。ASP8062 对 REM 睡眠时间没有影响。帕罗西汀对 SWS 没有影响，但显著缩短了 REM 睡眠时间。还观察到 ASP8062 引起 GH 释放的剂量依赖性增加趋势。ASP8062 最常见的治疗后出现的不良事件（TEAEs）是头痛和恶心；大多数 TEAEs 为轻度。
单剂量 ASP8062（35 和 70mg）似乎导致中枢神经系统渗透和增强 GABA 能活性，表现为慢波睡眠和生长激素释放增加。
