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 药物过量引起的呼吸抑制，如果不加以治疗，可引起严重的危及生命的并发症， 包括呼吸停止和死亡阿片类药物过量导致的物质诱导的呼吸抑制， 其他中枢神经系统抑制剂，如镇静剂和酒精，以及越来越多的多种物质滥用 是造成死亡的主要原因，并随着麻醉品消费的显著增加而增加。 ENA-001是一种刺激通气的治疗剂-而不会逆转镇痛作用，或促进呼吸系统的恢复。 停药-用于治疗呼吸和中枢神经系统（CNS）抑制患者， 在医院或社区环境中阿片类药物或多种物质过量。这是一种新的化合物， 被归类为新化学实体。兴奋剂的主要分子机制 ENA-001的作用似乎是对颈动脉体的BK通道的功能性抑制，从而充当一种抑制剂。 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。 在两项递增剂量研究以建立IV输注的剂量范围后，连续输注ENA-200。 001被证明在强阿片类药物（阿芬太尼）的存在下刺激呼吸，同时保留 阿芬太尼的镇痛作用。ENA-001维持氧饱和度和ETCO 2在正常范围内（P <0.05）。 0.05，P < 0.01），MV大于安慰剂（p < 0.01）。下一个发展阶段 是表征肌肉内（IM）和静脉内（IV）推注（快速给药）的有效性 在诊所或社区环境中疑似用药过量的给药途径。在本提案中，Enalare将 在健康志愿者群体中研究IV推注和IM ENA-001的PK/PD和功效。相1 使用模型知情药物开发（MIDD）确定Aim初始IM和IV推注给药的PK/PD研究 2. MIDD过程将使用来自多项IV连续输注研究的现有PK和PD数据， 沿着来自临床前IM和IV推注输送模型的数据，例如最近完成的IM 生物利用度研究和正在进行的IM生物等效性研究，以确定剂量目标， 获得有效的血浆药物暴露，从而从推注给药获得最佳的治疗效果（功效）。 II期将是一项安全性、耐受性、药代动力学和 以IM和IV推注施用的ENA-001的药效学。研究方案为8个阶段 递增、重复、单剂量、安全性和耐受性研究，比较ENA-001与安慰剂的作用 在2组筛选的健康志愿者中。研究阶段将进行IM（4个阶段）和IV（4个阶段） 推注，并将进行随机化、双盲和安慰剂对照。所得到的资料 这一建议将用于定义模拟阿片类药物诱导的呼吸系统疾病的后续有效性研究。 并将提供关于IM和IV ENA-001推注对通气的疗效的充分信息 并尽可能地模仿现实生活（即，街道）条件。

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.