Accelerated Development of Lofexidine for Neonatal Opioid Withdrawal Syndrome

洛非西定的加速开发用于治疗新生儿阿片类药物戒断综合征

• 批准号: 9788408
• 负责人: Kristen Leann Gullo
• 金额: $ 233万
• 依托单位: US WORLDMEDS, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788408
• 关键词: Adolescent; Adrenergic Agonists; Adrenergic Receptor; Adult; Animals; Benzodiazepines; Biological Availability; Birth; Blood; Brain; Caring; Childhood; Clinical Research; Clinical Trials; Clinical assessments; Collaborations; Cytoplasmic Granules; Data; Deglutition; Development; Distress; Dosage Forms; Dose; Drug Kinetics; Drug Prescriptions; Drug user; Effectiveness; Ensure; Epidemic; Exposure to; Fees; Female; Formulation; General Population; Goals; Government; Grant; Growth; Health Care Costs; Healthcare Systems; Human; Incidence; Infant; Intervention; Investigation; Label; Length of Stay; Literature; Manufactured Materials; Medical; Metabolism; National Institute of Drug Abuse; Neonatal; Neonatal Abstinence Syndrome; Neurologic; Opioid; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Phase III Clinical Trials; Production; Program Development; Rattus; Receptor Activation; Reporting; Reproductive system; Research; Rodent Model; Role; Safety; Symptoms; Systems Development; Tablets; Testing; Toxic effect; Toxicokinetics; Toxicology; United Kingdom; United States; United States Food and Drug Administration; Withdrawal; Work; care costs; comparative; cost; human subject; in utero; inpatient service; lofexidine; neonatal brain; neonatal patient; neonate; nervous system development; neurodevelopment; non-opioid analgesic; novel therapeutics; off-label use; opioid abuse; opioid epidemic; opioid use; opioid withdrawal; patient population; pregnant; programs; public health emergency; reconstitution; reproductive development; safety study; scale up; volunteer

PROJECT SUMMARY: Over the past decade, rates of opioid use among the general population has continued to rise in the United States. This astounding increase in opioid use has resulted in the government declaring a public health emergency in 2017. Compounding the problem, a concurrent rise in opioid use among pregnant females has resulted in a massive increase in infants born suffering from opioid withdrawal, termed Neonatal Opioid Withdrawal Syndrome (NOWS). The NOWS epidemic has led to significant increases in healthcare costs and burden on the healthcare system due to increased length of hospital stay and level of required care. A normal infant averages 2.1 days of hospital care post-birth costing $3,500, whereas an infant born with NOWS averages 16.9 days of inpatient care costing $66,700. Currently, there are no FDA-approved medications available for treatment of NOWS. US WorldMeds (USWM) has developed lofexidine in collaboration with NIDA for the treatment of opioid withdrawal in adults, and anticipates possible Food and Drug Administration (FDA) approval for this use in May 2018. USWM now proposes to extend this successful co-development program through investigation of the safety and efficacy of lofexidine in NOWS. This application proposes a strategic alliance between USWM and the National Institute on Drug Abuse (NIDA) to complete development and registration prerequisites prior to initiation of clinical assessment of lofexidine in the neonatal patient population. The FDA has requested that USWM develop and establish safety information on lofexidine for neonate patient use. Initial requirements for registration of lofexidine for pediatric use are clearly defined and agreed upon with the FDA and include a total of five nonclinical studies in animals, seven clinical studies, and commitment to developing a pediatric specific formulation. The overall goal of this project is to develop a strategic alliance with NIDA and leverage this partnership to accelerate the development of the pediatric lofexidine program, with specific emphasis on the activities relevant for NOWS development. The research strategy in this proposal specifically targets the FDA requested development of lofexidine for NOWS treatment and will be supported by: 1) the development, scale up, and clinical trial material production of a neonatal-appropriate lofexidine formulation (Specific Aims 1 and 5), 2) completion of pivotal nonclinical studies to establish safety margins in nonclinical juvenile rodent models considered appropriate to assess safety related to early brain development and general toxicity (Specific Aims 2, 3, and 4), and 3) completion of a comparative bioavailability study with adult and pediatric formulations in normal healthy adult volunteers (Specific Aim 6).

项目总结： 在过去十年中，美国普通人群中阿片类药物的使用率持续上升。 各州。阿片类药物使用量的惊人增长导致政府宣布公共卫生 2017年进入紧急状态。使问题雪上加霜的是，怀孕女性中阿片类药物的使用量同时上升 导致出生时阿片类药物戒断的婴儿数量大幅增加，被称为新生儿阿片类药物 戒断综合症(NOWS)。NOWS疫情导致医疗费用大幅增加， 由于住院时间和所需护理水平的增加，给医疗保健系统带来了负担。一个正常的 婴儿出生后平均2.1天的住院护理费用为3500美元，而出生时患有NOWS的婴儿平均 16.9天的住院护理费用为66,700美元。目前，没有FDA批准的药物可用于 对NOWS的处理。美国WorldMeds(USWM)与NIDA合作开发了洛非西定 成人阿片类药物戒断的治疗，并预计可能获得食品和药物管理局(FDA)的批准 于2018年5月用于此用途。USWM现在提议通过以下方式扩展这一成功的共同开发计划 洛非西定治疗NOWS的安全性和有效性研究本申请提出了一项战略联盟 USWM与国家药物滥用研究所(NIDA)合作完成开发和注册 在新生儿患者人群中开始洛非西定临床评估之前的先决条件。 FDA要求USWM开发和建立用于新生儿患者的洛非西定的安全信息 使用。明确规定了儿科用洛非西定的初始注册要求，并与 FDA，包括总共5项动物非临床研究，7项临床研究，并承诺 开发一种儿科专用配方。该项目的总体目标是与 NIDA和利用这一伙伴关系加快儿科洛非西定计划的发展， 特别强调与NOWS开发相关的活动。这份提案中的研究策略 专门针对FDA要求开发的用于NOWS治疗的洛非西定，并将得到以下支持： 1)适合新生儿的洛非西定的开发、放大和临床试验材料的生产 制定(具体目标1和5)，2)完成关键的非临床研究，以确定安全边际 非临床幼年啮齿动物模型被认为适合于评估与早期脑发育有关的安全性 和一般毒性(特定目标2、3和4)，以及3)完成与 正常健康成人志愿者的成人和儿科制剂(特定目标6)。