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.

项目总结