Development of medication for the treatment of respiratory depression due to opioid (prescribed or illicit) overdose/multidrug (polysubstance) overdose in a hospital or community setting.

摘要 药物过量导致的呼吸抑制，如果不治疗，可能会导致严重的危及生命的并发症， 包括呼吸停止和死亡。过量阿片类药物引起的呼吸抑制， 其他中枢神经系统抑制药，如镇静剂和酒精，以及越来越多的多物质滥用 是导致死亡的主要原因，并且与麻醉药品消费的显著增加同步上升。 ENA-001是一种促进通风的治疗剂，不会逆转止痛效果，也不会沉淀 停药-用于治疗因以下原因而导致的呼吸和中枢神经系统(CNS)抑郁患者 医院或社区环境中的阿片类药物或多药过量。这是一种新的化合物，有望 被归类为一个新的化学实体。呼吸性兴奋剂的主要分子机制 ENA-001的作用似乎是功能性地抑制颈动脉小体的BK通道，从而起到 模拟缺氧。ENA-001已经在四项临床研究中用于人类，第五项正在进行中。 在进行了两次剂量递增研究以建立静脉输液的剂量范围后，持续输注ENA- 001被证明在强阿片类药物(阿芬太尼)存在的情况下刺激呼吸，同时保持 阿芬太尼的镇痛作用。ENA-001维持血氧饱和度和ETCO2在正常范围内(P&lt； 0.05，P&lt；0.01，分别与安慰剂相比)，MV大于安慰剂(P&lt；0.01)。发展的下一个阶段 是表征肌肉(IM)和静脉(IV)团注(快速剂量)的适当疗效 诊所或社区环境中疑似过量用药的给药途径。在这项提案中，Enalare将 研究静脉推注和肌注ENA-001对健康志愿者的PK/PD和疗效的影响。第一阶段是 使用模型知情药物开发(MIDD)进行PK/PD研究以确定AIM的初始肌注和静脉推注剂量 2.MIDD过程将使用来自#年多次静脉持续输液研究的现有PK和PD数据 人类，以及来自临床前IM和静脉推注模型的数据，如最近完成的IM 生物利用度研究和正在进行的肌注生物等效性研究，以确定给药目标，以实现快速 通过团注获得有效的血浆药物暴露，从而获得最佳的治疗效果(效果)。 第二阶段将是安全性、耐受性、药代动力学和 ENA-001肌注和静脉推注的药效学。研究方案为8个周期 ENA-001与安慰剂疗效的递增、重复、单次给药、安全性和耐受性研究 在两组经过筛选的健康志愿者中。学习时间为IM(4节)和IV(4节) 团注，并将随机、双盲和安慰剂对照。从以下方面获得的信息 这项提议将被用来定义在阿片类药物诱导的呼吸模拟中的有效性的后续研究 并将提供充分的信息，说明肌注和静脉注射ENA-001对呼吸机的疗效 并尽可能地模仿现实生活(即街道)的情况。

ABSTRACT Respiratory depression from drug overdose, if untreated, can cause serious life-threatening complications, including respiratory arrest and death. Substance-induced respiratory depression from overdose of opioids, other central nervous system depressants such as sedatives and alcohol, and increasingly polysubstance abuse is a leading cause of mortality and has risen in parallel with the marked increase in narcotics consumption. ENA-001 is a therapeutic agent which stimulates ventilation – without reversing analgesic effects, or precipitating withdrawal – for treatment of patients with respiratory and central nervous system (CNS) depression due to opioid or polysubstance overdose in a hospital or community setting. It is a novel compound that is expected to be classified as a New Chemical Entity. The primary molecular mechanism underlying the ventilatory stimulant effects of ENA-001 appears to be functional inhibition of BK channels of the carotid bodies, thereby acting as a hypoxia-mimetic. ENA-001 has been administered to humans during four clinical studies, with a fifth underway. Following two ascending dose studies to establish a dosing range for IV infusion, a continuous infusion of ENA- 001 was shown to stimulate respiration in the presence of a strong opioid (alfentanil) while preserving the analgesic effects of alfentanil. ENA-001 maintained oxygen saturation and ETCO2 within normal range (P < 0.05, P < 0.01, respectively vs placebo) with greater MV than placebo (p < 0.01). The next stage in development is to characterize the efficacy of intramuscular (IM) and intravenous (IV) bolus injections (rapid dosing) as suitable routes of administration for suspected overdose in the clinic or community setting. In this proposal, Enalare will study the PK/PD and efficacy of IV bolus and IM ENA-001 in a population of healthy volunteers. Phase 1 is PK/PD studies using Model Informed Drug Development (MIDD) to identify initial IM and IV bolus dosing for Aim 2. The MIDD process will use existing PK and PD data from the multiple IV continuous infusion studies in humans, along with data from preclinical IM and IV bolus delivery models such as the recently completed IM bioavailability study and ongoing IM bioequivalence study, to determine dosing targets to achieve rapid attainment of effective plasma drug exposure, thus optimal therapeutic effects (efficacy), from bolus dosing. Phase 2 will be a Single Ascending Dose Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ENA-001 administered as IM and IV bolus injections. The study protocol is an 8-period ascending, repeated, single dose, safety and tolerability study comparing the effects of ENA-001 with placebo in 2 panels of screened healthy volunteers. Study periods will be conducted for IM (4-periods) and IV (4-periods) bolus injections, and will be randomized, double-blinded, and placebo-controlled. The information gained from this proposal will be used to define subsequent studies of efficacy in simulations of opioid-induced respiratory depression and will give ample information on the efficacy of IM and IV ENA-001 bolus injections on ventilation and mimics, as much as possible, real-life (i.e., street) conditions.