Sunovion Pharmaceuticals Inc, Marlborough, MA, USA.
Transl Psychiatry. 2021 Apr 20;11(1):228. doi: 10.1038/s41398-021-01331-9.
SEP-363856 is a trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT) agonist, currently in Phase 3 clinical trials for the treatment of schizophrenia. Although SEP-363856 activates TAAR1 and 5-HT receptors in vitro, an accessible marker of time- and concentration-dependent effects of SEP-363856 in humans is lacking. In rodents, SEP-363856 has been shown to suppress rapid eye movement (REM) sleep. The aim of the current study was to translate the REM sleep effects to humans and determine pharmacokinetic/pharmacodynamic (PK/PD) relationships of SEP-363856 on a measure of brain activity. The effects of SEP-363856 were evaluated in a randomized, double-blind, placebo-controlled, 2-way crossover study of single oral doses (50 and 10 mg) on REM sleep in healthy male subjects (N = 12 at each dose level). Drug concentrations were sampled during sleep to interpolate individual subject's pharmacokinetic trajectories. SEP-363856 suppressed REM sleep parameters with very large effect sizes (>3) following single doses of 50 mg and plasma concentrations ≥100 ng/mL. Below that effective concentration, the 10 mg dose elicited much smaller effects, increasing only the latency to REM sleep (effect size = 1). The PK/PD relationships demonstrated that REM sleep probability increased as drug concentrations declined below 100 ng/mL over the course of the night. SEP-363856 was generally safe and well tolerated at both doses. The REM sleep-suppressing effects of SEP-363856 provide an accessible marker of brain activity, which can aid in dose selection and help elucidate its therapeutic potential in further clinical trials.
SEP-363856 是一种追踪胺相关受体 1（TAAR1）和 5-羟色胺 1A 型（5-HT）激动剂，目前正处于治疗精神分裂症的 3 期临床试验阶段。尽管 SEP-363856 在体外激活 TAAR1 和 5-HT 受体，但缺乏人类中 SEP-363856 时间和浓度依赖性作用的可及标志物。在啮齿动物中，已显示 SEP-363856 抑制快速眼动（REM）睡眠。本研究的目的是将 REM 睡眠效应转化为人类，并确定 SEP-363856 在大脑活动测量中的药代动力学/药效学（PK/PD）关系。在一项健康男性受试者（每个剂量水平 12 名）的随机、双盲、安慰剂对照、2 向交叉研究中，评估了 SEP-363856 对 REM 睡眠的单口服剂量（50 和 10mg）的影响。在睡眠期间采样药物浓度以内插个体受试者的药代动力学轨迹。在单次剂量为 50mg 和血浆浓度≥100ng/mL 时，SEP-363856 抑制 REM 睡眠参数，具有非常大的效应大小（>3）。在低于该有效浓度下，10mg 剂量引起的作用较小，仅增加 REM 睡眠潜伏期（效应大小=1）。PK/PD 关系表明，随着药物浓度在夜间低于 100ng/mL 下降，REM 睡眠的可能性增加。SEP-363856 在两个剂量下均通常安全且耐受良好。SEP-363856 的 REM 睡眠抑制作用提供了大脑活动的可及标志物，这有助于选择剂量并帮助阐明其在进一步临床试验中的治疗潜力。
