Abuse-deterrence and prevention of respiratory depression by an oral opioid analgesic and doxapram combination

项目总结 虽然阿片类药物是最有效的止痛药，但它们用于止痛通常会发展为阿片类药物。 使用无序(OUD)。阿片类药物过量死亡(每天有115名美国人)在大多数情况下是由阿片类药物过量引起的 通过阿片类药物诱导的呼吸抑制(OIRD)。保留所需止痛剂的新阿片制剂 但缺乏致命的呼吸道和不想要的成瘾作用，仍然是一个未得到满足的临床需求。 Quivive Pharma正在开发首个可立即释放的阿片类药物配方，可预防呼吸道感染 抑郁保护和滥用-威慑性能，其中包含普通阿片氢可酮(HC)， 与FDA批准的呼吸兴奋剂多沙普兰(DOX)的亚治疗剂量相结合。这个 独特的配方设计，提供有效的疼痛缓解，降低OIRD的风险。除了……之外 提高安全性，DOX通过产生令人不快但并不危险的焦虑症来起到威慑滥用的作用 在过度消费滥用的情况下的影响，同时对阿片类药物的镇痛没有负面影响 治疗范围。Quivive Pharma已完成体内疗效研究以及广泛的临床前研究 IND前与FDA会议后的安全性和药代动力学(PK)研究。无不良临床症状 已经在口服DOX治疗的大鼠、狗或猴子中发现了这种情况。取得的可喜成果 到目前为止，支持这种对SBIR阶段II应用程序的直接访问，以执行首次人工验证 建议的方法。特别是，一项单次递增剂量(SAD)概念验证临床研究 将对35名健康、非依赖、娱乐性阿片类药物使用者进行HC治疗 与克利夫兰诊所的合作。这项研究将首次评估安全性、耐受性和 联合用药在人体内的药效学。安全评估(目标1)将包括 监测不良事件和生命体征。此外，血清化学、血液学和尿液分析也将 同时进行体格检查和心电监测。最后，病人 被录取的学生将完成哥伦比亚自杀严重程度评定量表问卷，以评估自杀倾向。A主键 评估(目标2)将证明HC的血浆PK不受DOX联合治疗的影响， 口服DOX暴露随着剂量的增加而增加，达到最大值的时间 DOX浓度与HC浓度基本一致。药效学评估(包括 呼吸功能、药物喜好和瞳孔大小的评估)将使确定最佳DOX成为可能 安全地对抗HC引起的呼吸抑制的剂量(目标3)。在圆满完成这项工作后 SBIR第二阶段项目，DOX与HC联合给药的多个递增剂量研究 将对依赖的、娱乐的阿片类药物使用者进行检查，以确保本文件中确定的HC/DOX比率 在反复给药后，受试者对研究有很好的耐受性。

PROJECT SUMMARY While opioids are the most effective pain-killers, their use for pain management often develops into an opioid use disorder (OUD). Death from an opioid overdose (by 115 Americans every day) is in most cases caused by opioid-induced respiratory depression (OIRD). A new opioid formulation that retains the desired analgesic properties but lacks deadly respiratory and unwanted addictive effects, remains an unmet clinical need. Quivive Pharma is developing the first immediate-release opioid formulation with both prophylactic respiratory depression protection and abuse-deterrent properties, which contains the generic opioid Hydrocodone (HC), combined with a sub-therapeutic dose of the FDA-approved respiratory stimulant Doxapram (DOX). The unique formulation is designed to deliver effective pain relief with decreased risk of OIRD. In addition to improving safety, DOX serves as an abuse-deterrent by producing unpleasant, but not dangerous, anxiogenic effects in case of abuse by overconsumption, while having no negative impact on opioid analgia in the therapeutic range. Quivive Pharma has completed in vivo efficacy studies as well as extensive preclinical safety and pharmacokinetics (PK) studies following a Pre-IND meeting with FDA. No adverse clinical signs have been noted in rats, dogs, or monkeys following oral treatment with DOX. The promising results achieved so far support this direct access to an SBIR Phase II application to perform a first in human validation of the proposed approach. In particular, a single ascending dose (SAD) proof-of-concept clinical study of DOX co- administered with HC will be performed with 35 healthy, non-dependent, recreational opioid users in collaboration with the Cleveland Clinic. This study will assess for the first time the safety, tolerability, and pharmacodynamics of the combination drug in human subjects. The safety evaluation (Aim 1) will include the monitoring of Adverse Events (AEs) and vital signs. Also, serum chemistry, hematology, and urinalysis will be performed together with physical examinations and electrocardiogram monitoring. Finally, patients enrolled will complete the Columbia Suicide Severity Rating Scale questionnaire to assess suicidality. A PK assessment (Aim 2) will demonstrate that Plasma PK of HC is unaffected by the combination with DOX, the exposure of oral DOX increases with the dose administered, and the time to reach the maximum concentration of DOX is consistent with that of HC. The pharmacodynamics assessments (including evaluation of respiratory function, drug liking, and pupil size) will enable the identification of the optimal DOX dose to safely counteract HC-induced respiratory depression (Aim 3). After the successful completion of this SBIR Phase II project, a Multiple Ascending Dose Study of DOX co-administered with HC in healthy, non- dependent, recreational opioid users will be performed to ensure that the HC/DOX ratios identified in this study are well tolerated in human subjects following repeated administration.