与吗啡相比，TRV130对μ-阿片受体的选择性激活能加强止痛同时减轻目标副反应

与吗啡相比，TRV130对μ-阿片受体的选择性激活能加强止痛同时减轻目标副反应：一项基于健康志愿者的随机、双盲、安慰剂对照、交叉研究

Biased agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteers

阿片类药物通过激活μ-阿片受体，能提供强有力的止痛作用，但同时产生会限制疗效的不良反应，包括严重的恶心、呕吐和呼吸抑制。临床前模型显示，激活不同的受体下游信号通路可以将止痛作用和不良反应分离开来，但至今未能通过某个改良的治疗指标将其转换为一种治疗措施。在一项随机、双盲、交叉研究中，30名健康男性分别静脉注射了单剂量的选择性配体TRV130（1.5, 3，或4.5mg），安慰剂或吗啡（10mg）。研究的主要目标是与安慰剂相对照，测定药物的安全性、耐受性（不良事件，生命体征，心电图，临床实验室指标）和止痛作用（冷疼痛测试）。其他测量指标包括呼吸动力（诱导高碳酸血症后的分钟通气量），主观药物作用以及药代动力学。与吗啡相比，TRV130（3, 4.5mg）能形成更高的镇痛峰（冷痛耐受时间105s，116s vs 吗啡75s，P<.02），起效更快，且作用时间相似。TRV130 (3, 4.5mg)受试者耐受时间翻番或达到耐受时间测试上限（180秒）的情况更为多见。与任何剂量的TRV130相比，吗啡更容易引起呼吸动力的下降（吗啡-15.9 h*L/min vs TRV130 -7.3, -7.6, and -9.4 h*L/min，P<.05）。吗啡受试者中出现严重呕吐比TRV130 1.5 或 3mg多，但比TRV130 4.5mg少。TRV130的一般耐受性良好，且毒性与剂量呈正比。因此，在该研究中，与吗啡相比，TRV130体现出更好的止痛效果、较低的呼吸抑制和较少的严重呕吐。该研究提示配体选择性的早期临床转化可以作为受体靶向药物治疗中的一个新的重要概念。

Opioids provide powerful analgesia but also efficacy-limiting adverse effects, including severe nausea, vomiting, and respiratory depression, by activating μ-opioid receptors. Preclinical models suggest that differential activation of signaling pathways downstream of these receptors dissociates analgesia from adverse effects; however, this has not yet translated to a treatment with an improved therapeutic index. Thirty healthy men received single intravenous injections of the biased ligand TRV130 (1.5, 3, or 4.5mg), placebo, or morphine (10mg) in a randomized, double-blind, crossover study. Primary objectives were to measure safety and tolerability (adverse events, vital signs, electrocardiography, clinical laboratory values), and analgesia (cold pain test) versus placebo. Other measures included respiratory drive (

minute volume after induced hypercapnia), subjective drug effects, and pharmacokinetics. Compared to morphine, TRV130 (3, 4.5mg) elicited higher peak analgesia (105, 116seconds latency vs 75seconds for morphine, P<.02), with faster onset and similar duration of action. More subjects doubled latency or achieved maximum latency (180seconds) with TRV130 (3, 4.5mg). Respiratory drive reduction was greater after morphine than any TRV130 dose (-15.9 for morphine versus -7.3, -7.6, and -9.4 h*L/min, P<.05). More subjects experienced severe nausea after morphine (n=7) than TRV130 1.5 or 3mg (n=0, 1), but not 4.5mg (n=9). TRV130 was generally well tolerated, and

exposure was dose proportional. Thus, in this study, TRV130 produced greater analgesia than morphine at doses with less reduction in respiratory drive and less severe nausea. This demonstrates early clinical translation of ligand bias as an important new concept in receptor-targeted pharmacotherapy.