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

项目摘要 虽然阿片类药物是最有效的止痛药，但其用于疼痛管理的用途往往发展成为阿片类药物 使用障碍（OUD）。阿片类药物过量（每天115名美国人）导致的死亡在大多数情况下是由 阿片类药物引起的呼吸抑制（OIRD）一种新的阿片类药物制剂，保留了所需的镇痛剂 但没有致命的呼吸和不需要的成瘾作用，仍然是一个未满足的临床需求。 Quivive Pharma正在开发第一种速释阿片类药物制剂， 抑郁症保护和滥用威慑特性，其中含有通用阿片类药物氢可酮（HC）， 与亚治疗剂量的FDA批准的呼吸兴奋剂多沙普仑（DOX）结合。的 独特的配方设计，提供有效的疼痛缓解，降低OIRD的风险。除了 提高安全性，DOX通过产生令人不快但不危险的焦虑， 在过度消费滥用情况下的影响，同时对阿片类镇痛没有负面影响， 治疗范围。Quivive Pharma已经完成了体内疗效研究以及广泛的临床前研究。 与FDA召开IND前会议后进行的安全性和药代动力学（PK）研究。无不良临床体征 在大鼠、狗或猴中，在口服DOX治疗后已经注意到。取得的可喜成果 到目前为止，支持直接访问SBIR第二阶段应用程序，以执行首次人工验证 建议的方法。特别是，一项DOX共治疗的单次递增剂量（SAD）概念验证临床研究， 将在35名健康、非依赖性、娱乐性阿片类药物使用者中进行HC给药， 与克利夫兰诊所合作。这项研究将首次评估安全性、耐受性和 在人类受试者中的组合药物的药效学。安全性评价（目标1）将包括 监测不良事件（AE）和生命体征。此外，血清化学、血液学和尿分析将 与体格检查和心电图监测同时进行。最后，患者 入选者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。的PK 评估（目标2）将证明HC的血浆PK不受与DOX的组合的影响， 口服DOX的暴露量随着给药剂量和达到最大剂量的时间而增加。 DOX的浓度与HC的浓度一致。药效学评估（包括 呼吸功能、药物喜好和瞳孔大小的评估）将能够识别最佳DOX 安全抵消HC诱导的呼吸抑制的剂量（目的3）。在成功完成这项工作后， SBIR II期项目，一项在健康、非肥胖和肥胖人群中进行的DOX与HC联合给药的多次递增剂量研究。 依赖性，娱乐性阿片类药物使用者将进行，以确保HC/DOX比率确定在此 研究表明，重复给药后，受试者的耐受性良好。

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.