Evaluation of safety and pharmacokinetics of naltrexone implant

纳曲酮植入剂的安全性和药代动力学评价

• 批准号: 9917086
• 负责人: ADAM BISAGA
• 金额: $ 10.14万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9917086
• 关键词: Address; Adherence; Australia; Blood; Buprenorphine; Clinical; Consultations; Controlled Clinical Trials; Data; Development; Dose; Drug Kinetics; Effectiveness; Evaluation; Formulation; Goals; Implant; Individual; Injections; Medical; Methadone; Methods; Miniature Swine; Modeling; Naltrexone; Names; National Institute of Drug Abuse; Opioid; Opioid Receptor; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Randomized; Relapse; Research Personnel; Safety; Sample Size; Therapeutic; Therapeutic Equivalency; Tissues; Toxic effect; comparative effectiveness; disorder later incidence prevention; implantation; innovation; novel therapeutics; opioid epidemic; opioid mortality; opioid use disorder; premature; prototype; safety testing; subcutaneous

New medication treatment approaches are needed to help address the severe epidemic of opioid use disorder (OUD) and opioid overdose deaths in the US. Currently available medications, methadone, buprenorphine, and extended release injection naltrexone (XR-NTX; trade name: Vivitrol), are highly efficacious, but their effectiveness in practice is limited by poor adherence, with many patients stopping treatment prematurely and relapsing. The goal of this proposal is to develop an innovative long acting subcutaneous implanted formulation of naltrexone, the O’Neil Long-Acting Naltrexone Implant (OLANI), towards FDA approval. Expected to produce naltrexone blood levels sufficient to block the effects of opioids for 6 months after implant, OLANI circumvents the need for adherence to monthly injections with XR-NTX, and could represent an important new addition to the medical armamentarium for treatment of OUD. The OLANI has been in development by an Australian company Go Medical for 20 years with several prototypes evaluated in controlled clinical trials and used clinically in Australia. The current formulation has higher drug loading and a better release profile and is manufactured in a GMP facility. It has been used clinically in over 800 patients, giving confidence that the product can be successfully developed in the US. Go Medical and the current team of investigators met with the FDA to chart a development path towards a New Drug Application (NDA) via the 505 b(2) pathway with Vivitrol as a comparator product. An application for an IND (# 134996) is under review by the FDA. This proposal seeks NIDA’s support under the UG3/UH3 mechanism to conduct the studies recommended by the FDA for the 505 b(2) pathway to approval. Under the UG3 Phase, Study 1 will evaluate local tissue toxicity of OLANI in a minipig model, and Study 2 will generate pilot pharmacokinetic (PK) data of OLANI in healthy subjects in order to determine power and finalize sample size for a subsequent bioequivalence (BE) study and to support feasibility and tolerability. If there are no safety concerns and naltrexone blood levels are adequate in the UG3 phase, then in the UH3 phase (Study 3) will be finalized in consultation with NIDA and FDA. Study 3 will compare 6-month PK of OLANI versus XR-NTX as the reference drug to establish bioequivalence (BE) in terms of naltrexone blood levels, safety and comparative effectiveness in patients with OUD. Patients will be randomized to receive either a single subcutaneous implantation of 3.6g dose of OLANI or repeat doses of Vivitrol 380 mg IM q4 weeks for 24 weeks. Participants randomized to OLANI will be offered an additional implant at month 6. We hypothesize that OLANI will have a systemic exposure (Cmax,Cmin,AUC0-180) and MEC of naltrexone blood levels comparable to XR-NTX. If OLANI is shown to provide a safe, feasible and effective method of delivery of naltrexone at therapeutic levels for at least 6 months, it would represent a major advance in the field of OUD treatment, providing effective long term relapse-prevention treatment to individuals with OUD.

需要新的药物治疗方法来帮助解决阿片类药物使用的严重流行。 美国的精神障碍和阿片类药物过量死亡。目前可用的药物，美沙酮， 丁丙诺啡和缓释注射用纳曲酮(XR-NTX；商品名：Vivitrol) 有效，但在实践中的有效性受到依从性差的限制，许多患者停用 过早治疗和复发。这项提议的目标是开发一种创新的长效 皮下植入的纳曲酮配方，奥尼尔长效纳曲酮植入剂(OLANI)， 接近FDA的批准。预计将产生足以阻断阿片类药物影响的纳曲酮血液水平 在植入后的6个月内，Olani无需每月注射XR-NTX，并且 可能代表着治疗OUD的医疗设备中的一个重要的新成员。 奥拉尼已经由一家澳大利亚公司Go Medical开发了20年，有几个 原型在对照临床试验中进行了评估，并在澳大利亚临床上使用。目前的提法有 更高的载药量和更好的释放情况，并在GMP设施中生产。它已经被使用了 在800多名患者的临床应用中，使人们有信心该产品可以在美国成功开发。去 医疗和目前的调查团队与FDA会面，制定了一条通往新的 药物应用(NDA)通过505b(2)途径，以Vivitrol为对照产品。一份申请 IND(#134996)正在接受食品和药物管理局的审查。该提案寻求NIDA在UG3/UH3下的支持 进行FDA推荐的505b(2)途径批准研究的机制。 在UG3阶段，研究1将在小型猪模型中评估Olani的局部组织毒性，以及 研究2将生成Olani在健康受试者中的先导药代动力学(PK)数据，以确定功率 并最终确定用于后续生物等效性(BE)研究的样本量，以支持可行性和耐受性。 如果没有安全问题，并且纳曲酮水平在UG3阶段充足，那么在UH3阶段 阶段(研究3)将在与NIDA和FDA协商后最后敲定。研究3将比较6个月的PK OLANI与XR-NTX作为参考药物建立纳曲酮血液生物等效性(BE) OUD患者的水平、安全性和相对有效性。患者将被随机接受 单次皮下注射3.6g奥拉尼或重复剂量维维特罗380 mg肌注Q4 连续24周。被随机分配到Olani的参与者将在6个月时获得额外的植入物。 假设Olani将有全身暴露(Cmax，Cmin，AUC0-180)和MEC的纳曲酮血液 水平与XR-NTX相当。如果奥拉尼被证明提供了一种安全、可行和有效的分娩方法 纳曲酮的治疗水平至少6个月，这将是OUD领域的重大进展。 治疗，为OUD患者提供有效的长期预防复发治疗。