Accelerated Development of Lofexidine for Neonatal Opioid Withdrawal Syndrome

项目概要： 在过去十年中，美国普通人群中阿片类药物使用率持续上升， States.阿片类药物使用的惊人增加导致政府宣布公共卫生 2017年紧急。使问题更加复杂的是，孕妇使用阿片类药物的同时增加， 导致出生时患有阿片类药物戒断的婴儿大量增加，称为新生儿阿片类药物 戒断综合征（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，对医疗保健系统造成负担。正常 婴儿出生后平均住院治疗2.1天，花费3,500美元，而出生时患有NOWS的婴儿平均 16.9住院治疗天数花费66，700美元。目前，没有FDA批准的药物可用于 治疗NOWS美国WorldMeds（USWM）与NIDA合作开发了洛非西定， 治疗成人阿片类药物戒断，并预计可能获得食品和药物管理局（FDA）的批准 在2018年5月使用。USWM现在建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。本申请提出战略联盟 在USWM和国家药物滥用研究所（NIDA）之间完成开发和注册 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已要求USWM开发和建立洛非西定用于新生儿患者的安全性信息 使用.明确定义了儿科用洛非西定注册的初始要求，并与 包括总共五项动物非临床研究，七项临床研究，并承诺 开发儿科专用配方。该项目的总体目标是与 NIDA和利用这种伙伴关系，以加快发展的儿科洛非西定计划， 特别强调与发展NOWS有关的活动。本提案中的研究策略 专门针对FDA要求开发的用于NOWS治疗的洛非西定，并将得到以下方面的支持： 1)开发、放大和临床试验材料生产适合产妇的洛非西定 制剂（具体目标1和5），2）完成关键非临床研究，以确定 认为适合评估与早期脑发育相关的安全性的非临床幼龄啮齿动物模型 和一般毒性（具体目标2、3和4），以及3）完成与以下药物的比较生物利用度研究： 在正常健康成人志愿者中的成人和儿童制剂（具体目标6）。

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).