Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.
Parexel International GmbH, Berlin, Germany.
Br J Clin Pharmacol. 2020 Jul;86(7):1377-1386. doi: 10.1111/bcp.14251. Epub 2020 Mar 6.
The orexin system is involved in anxiety behaviour and corresponding physiological reactions and constitutes a target for treatment of anxiety disorders. ACT-539313 is a potent, selective orexin-1 receptor antagonist being developed for the treatment of anxiety disorders. This first-in-human study investigated its single-dose pharmacokinetics (PK) including food effect, pharmacodynamics (PD), safety and tolerability.
This double-blind, placebo-controlled, randomized study included 40 healthy male subjects. Ascending oral doses of 10-400 mg ACT-539313 were investigated in 5 dose groups of 8 subjects (of whom 2 received placebo per dose group). At 100 mg, subjects received ACT-539313 in fasted and fed conditions in a fixed sequential design. PK, PD (objective and subjective measures of sedation and effects on central nervous system), safety and tolerability were assessed.
In fasted conditions, ACT-539313 was rapidly absorbed (median time to maximum plasma concentration [C ] 0.7-3.5 h) and cleared from plasma with a mean terminal half-life of 3.3-5.7 h across dose levels. A 1.63-fold (90% confidence interval: 1.26-2.11) increase in C and no change in area under the concentration-time curve extrapolated to infinity was observed under fed compared to fasted conditions. No relevant PD signals were detected except for a trend of reduced saccadic peak velocity around time to C . The most commonly reported adverse events were somnolence and headache. All adverse events were transient and of mild or moderate intensity. No treatment-related effects on vital signs, clinical laboratory or 12-lead electrocardiogram were observed.
ACT-539313 exhibits good safety and tolerability at single doses of up to and including 400 mg that warrant further investigations.
食欲素系统参与焦虑行为和相应的生理反应，是治疗焦虑症的靶点。ACT-539313 是一种有效的、选择性的食欲素-1 受体拮抗剂，正在开发用于治疗焦虑症。这项首次人体研究调查了其单剂量药代动力学（PK），包括食物效应、药效学（PD）、安全性和耐受性。
这项双盲、安慰剂对照、随机研究纳入了 40 名健康男性受试者。采用 8 名受试者（每组 2 名接受安慰剂）的 5 个剂量组（10-400mg），递增口服给予 ACT-539313。在 100mg 时，采用固定顺序设计，在禁食和进食条件下给予 ACT-539313。评估 PK、PD（镇静的客观和主观指标以及对中枢神经系统的影响）、安全性和耐受性。
在禁食条件下，ACT-539313 吸收迅速（最大血浆浓度[C ]的中位数时间为 0.7-3.5h），在各剂量水平下，血浆清除半衰期平均为 3.3-5.7h。与禁食相比，进食条件下 C 增加 1.63 倍（90%置信区间：1.26-2.11），而 AUC 0-inf 无变化。除 C 时的扫视峰速度降低趋势外，未检测到相关 PD 信号。报告的最常见不良事件是嗜睡和头痛。所有不良事件均为一过性，且为轻度或中度。未观察到与治疗相关的生命体征、临床实验室或 12 导联心电图变化。
ACT-539313 在高达 400mg 及以下的单剂量下表现出良好的安全性和耐受性，值得进一步研究。
