van Lemmen Maarten, Dahan Albert, Hang Yaming, Jansen Simone C, Lu Hong, Naylor Melissa, Olsson Tina, Sheikh Sarah, Sullivan Danielle, Tolkoff Max, van der Schrier Rutger, van Velzen Monique, von Rosenstiel Philipp, Wu Rebecca L, Meyer Seetha
Department of Anesthesiology, Anesthesia & Pain Research Unit, Leiden University Medical Center, Leiden, The Netherlands.
Qualitative Clinical Pharmacology, Takeda Development Center Americas, Inc., Lexington, Massachusetts.
Anesthesiology. 2025 Apr 1;142(4):628-638. doi: 10.1097/ALN.0000000000005375. Epub 2025 Jan 13.
Orexin neuropeptides help regulate sleep/wake states, respiration, and pain. However, their potential role in regulating breathing, particularly in perioperative settings, is not well understood. TAK-925 (danavorexton), a novel orexin receptor 2-selective agonist, directly activates neurons associated with respiratory control in the brain and improves respiratory parameters in rodents undergoing fentanyl-induced sedation. This study assessed the safety and effect of danavorexton on ventilation in healthy men in an established remifentanil-induced respiratory depression model.
This single-center, double-blind, placebo-controlled, two-way crossover, phase 1 trial randomized (1:1) 13 healthy men to danavorexton (11 mg [low-dose], then 19 mg [high-dose]) or placebo, under remifentanil infusion, on two occasions separated by a 36-h or longer washout period. Remifentanil infusion was titrated under isohypercapnic conditions to achieve an approximately 30 to 40% decrease in minute ventilation (from approximately 20 to approximately 14 l/min) before danavorexton/placebo administration. Assessments included safety, ventilation measurements, sedation, and pain tolerance.
A total of four (30.8%) danavorexton-treated participants and one (8.3%) placebo-treated participant experienced treatment-emergent adverse events (all mild in severity). Insomnia, lasting 1 day, occurred in one participant, and was considered related to danavorexton. Compared with placebo, low- and high-dose danavorexton significantly increased ventilation variables (observed mean [95% CI] change, sensitivity analysis model-based P values) including minute volume (8.2 [95% CI, 5.0 to 11.4] and 13.0 [95% CI, 9.4 to 16.5] l/min), tidal volume (312 [95% CI, 180 to 443] and 483 [95% CI, 309 to 657] ml), and respiratory rate (3.8 [95% CI, 1.9 to 5.7] and 5.2 [95% CI, 2.7 to 7.7] breaths/min; all P < 0.001). High-dose danavorexton significantly decreased sedation on a visual analog scale (-29.7 [95% CI, -54.1 to -5.3] mm; P < 0.001) and the Richmond Agitation Sedation Scale (0.4 [95% CI, 0.0 to 0.7]; P < 0.001) compared with placebo. Improvements in respiratory variables continued beyond completion of danavorexton infusion. No significant differences in pain tolerance were observed between danavorexton doses or between danavorexton and placebo (approximately 13% increase from baseline; low dose, P = 0.491; high dose, P = 0.140).
Danavorexton has effects on respiration and wakefulness in an opioid-induced respiratory depression setting without reversing opioid analgesia.
食欲素神经肽有助于调节睡眠/觉醒状态、呼吸和疼痛。然而，它们在调节呼吸方面的潜在作用，尤其是在围手术期环境中，尚未得到充分了解。TAK-925（达纳沃雷克斯顿）是一种新型的食欲素受体2选择性激动剂，可直接激活大脑中与呼吸控制相关的神经元，并改善接受芬太尼诱导镇静的啮齿动物的呼吸参数。本研究在已建立的瑞芬太尼诱导的呼吸抑制模型中评估了达纳沃雷克斯顿对健康男性通气的安全性和效果。
这项单中心、双盲、安慰剂对照、双向交叉的1期试验将13名健康男性随机（1:1）分为达纳沃雷克斯顿组（11毫克[低剂量]，然后19毫克[高剂量]）或安慰剂组，在瑞芬太尼输注的情况下，分两次进行，两次之间间隔36小时或更长的洗脱期。在等碳酸血症条件下滴定瑞芬太尼输注量，以在给予达纳沃雷克斯顿/安慰剂之前使分钟通气量降低约30%至40%（从约20升/分钟降至约14升/分钟）。评估包括安全性、通气测量、镇静和疼痛耐受性。
共有4名（30.8%）接受达纳沃雷克斯顿治疗的参与者和1名（8.3%）接受安慰剂治疗的参与者出现治疗中出现的不良事件（均为轻度）。一名参与者出现持续1天的失眠，被认为与达纳沃雷克斯顿有关。与安慰剂相比，低剂量和高剂量的达纳沃雷克斯顿显著增加了通气变量（观察到的平均值[95%置信区间]变化，基于敏感性分析模型的P值），包括分钟通气量（分别为8.2[95%置信区间，5.0至11.4]和13.0[95%置信区间，9.4至16.5]升/分钟）、潮气量（分别为312[95%置信区间，180至443]和483[95%置信区间，309至657]毫升）和呼吸频率（分别为3.8[95%置信区间，1.9至5.7]和5.2[95%置信区间，2.7至7.7]次/分钟；所有P<0.001）。与安慰剂相比，高剂量的达纳沃雷克斯顿在视觉模拟量表上显著降低了镇静程度（-29.7[95%置信区间，-54.1至-5.3]毫米；P<0.001）以及里士满躁动镇静量表评分（0.4[95%置信区间，0.0至0.7]；P<0.001）。达纳沃雷克斯顿输注结束后，呼吸变量仍持续改善。达纳沃雷克斯顿各剂量之间或达纳沃雷克斯顿与安慰剂之间在疼痛耐受性方面未观察到显著差异（较基线增加约13%；低剂量，P = 0.491；高剂量，P = 0.140）。
在阿片类药物诱导的呼吸抑制情况下，达纳沃雷克斯顿对呼吸和觉醒有影响，但不会逆转阿片类药物镇痛作用。
