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

口服阿片类镇痛药和多沙普仑组合的滥用威慑和预防呼吸抑制

• 批准号: 10383180
• 负责人: PETER JEFFREY RIX
• 金额: $ 139.32万
• 依托单位: QUIVIVE PHARMA, INC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383180
• 关键词: Address; American; Americas; Analgesics; Barbiturates; Benzodiazepines; Blood gas; Body Temperature; Buprenorphine; Businesses; Canis familiaris; Carbon Dioxide; Chemistry; Chronic; Clinic; Clinical; Clinical Research; Collaborations; Diastolic blood pressure; Dose; Doxapram; Drug Combinations; Drug Kinetics; Electrocardiogram; Enrollment; Ensure; Evaluation; FDA approved; Formulation; Funding Opportunities; Generations; Health; Helping to End Addiction Long-term; Hematology; Hydrocodone; Hydromorphone; Legal; Maximum Tolerated Dose; Measures; Mediating; Medicine; Methadone; Monitor; Monkeys; National Institute of Drug Abuse; Opioid; Opioid Analgesics; Opioid replacement therapy; Oral; Outcome; Pain; Pain management; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Physical Examination; Physiologic pulse; Plasma; Prevention; Price; Property; Publishing; Pupil; Pupil light reflex; Questionnaires; Rattus; Relapse; Respiration; Respiratory Stimulants; Respiratory physiology; Risk; Safety; Sampling; Serum; Severities; Small Business Innovation Research Grant; Suicide; Technology; Therapeutic; Time; Urinalysis; Validation; Ventilatory Depression; Visual; adverse event monitoring; analog; depressive symptoms; design; efficacy study; first-in-human; human subject; improved; in vivo; meetings; mortality risk; novel therapeutics; opioid abuse; opioid epidemic; opioid mortality; opioid overdose; opioid use disorder; opioid user; pain relief; phase 2 study; preclinical safety; prescription opioid; prevent; prophylactic; respiratory; safety assessment; ventilation

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.

项目摘要 虽然阿片类药物是最有效的止痛药，但它们用于疼痛管理通常会发展为阿片类药物 使用障碍（OUD）。在大多数情况下 通过阿片类药物诱导的呼吸抑郁症（OIRD）。一种保留所需镇痛药的新阿片类药物配方 特性但缺乏致命的呼吸和不必要的成瘾作用，仍然是未满足的临床需求。 Quivive Pharma正在开发第一个立即释放的阿片类药物配方，两种预防性呼吸 抑郁症保护和滥用滥用的特性，其中包含普通阿片类氢可酮（HC）， 结合FDA批准的呼吸刺激剂Doxapram（DOX）的亚治疗剂量。这 独特的配方旨在提供有效的疼痛缓解，而Oird的风险降低。此外 提高安全性，DOX通过产生不愉快但不是危险的焦虑而作为滥用行为 在过度消费滥用的情况下，对阿片类药物分析没有负面影响的影响 治疗范围。 Quivive Pharma已完成体内功效研究以及广泛的临床前研究 安全与药代动力学（PK）研究与FDA预先会议后。没有不良临床体征 口服DOX后，已经在大鼠，狗或猴子中注意到。有希望的结果取得了 到目前为止 建议的方法。特别是，单一升剂剂量（悲伤）DOX共同的概念概念证明临床研究 由HC管理的35位健康，非依赖性，休闲阿片类药物的使用者将在 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 人类受试者中联合药物的药效学。安全评估（AIM 1）将包括 监测不良事件（AES）和生命体征。此外，血清化学，血液学和尿液分析还将 与身体检查和心电图监测一起进行。最后，病人 注册将完成哥伦比亚自杀严重程度评级量表问卷，以评估自杀性。 PK 评估（AIM 2）将证明HC的等离子PK不受与Dox的组合影响， 口服DOX的暴露随剂量的增加而增加，达到最大的时间 DOX的浓度与HC的浓度一致。药效学评估（包括 评估呼吸功能，药物喜欢和学生大小）将使最佳DOX识别 剂量可以安全抵消HC诱导的呼吸抑郁症（AIM 3）。成功完成后 SBIR II期项目，一项与HC共同管理的DOX的多次升级剂量研究 将执行依赖，休闲阿片类药物用户，以确保在此确定的HC/DOX比率 一再给药后，人类受试者的研究良好。