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: 10333110
• 负责人: ADAM BISAGA
• 金额: $ 410.9万
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10333110
• 关键词: Absorbable Implants; Address; Adherence; Agonist; Australia; Blood; Buprenorphine; Clinical; Consultations; Controlled Clinical Trials; Data; Development; Dose; Drug Kinetics; Effectiveness; Evaluation; FDA approved; Formulation; Goals; Grant; Histologic; Implant; Individual; Injections; Maintenance; Measures; Medical; Methadone; Methods; Miniature Swine; Modeling; Naltrexone; Names; National Institute of Drug Abuse; No-Observed-Adverse-Effect Level; Opioid; Opioid Receptor; Overdose; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Placebos; Randomized; Recovery; Relapse; Research Personnel; Safety; Saline; Sample Size; Testing; Therapeutic; Therapeutic Equivalency; Time; Tissues; Toxic effect; arm; comparative effectiveness; design; disorder later incidence prevention; healthy volunteer; implantation; individual variation; innovation; novel therapeutics; opioid epidemic; opioid mortality; opioid use disorder; opioid withdrawal; overdose prevention; premature; prototype; psychosocial; relapse risk; response; safety testing; sample collection; subcutaneous; Absorbable Implants; Address; Adherence; Agonist; Australia; Blood; Buprenorphine; Clinical; Consultations; Controlled Clinical Trials; Data; Development; Dose; Drug Kinetics; Effectiveness; Evaluation; FDA approved; Formulation; Goals; Grant; Histologic; Implant; Individual; Injections; Maintenance; Measures; Medical; Methadone; Methods; Miniature Swine; Modeling; Naltrexone; Names; National Institute of Drug Abuse; No-Observed-Adverse-Effect Level; Opioid; Opioid Receptor; Overdose; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Placebos; Randomized; Recovery; Relapse; Research Personnel; Safety; Saline; Sample Size; Testing; Therapeutic; Therapeutic Equivalency; Time; Tissues; Toxic effect; arm; comparative effectiveness; design; disorder later incidence prevention; healthy volunteer; implantation; individual variation; innovation; novel therapeutics; opioid epidemic; opioid mortality; opioid use disorder; opioid withdrawal; overdose prevention; premature; prototype; psychosocial; relapse risk; response; safety testing; sample collection; 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.

需要采用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 在美国，疾病（OUD）和阿片类药物过量死亡。目前可用的药物，元通， 丁丙诺啡和延长释放注射纳曲酮（XR-NTX；商品名：vivitrol）高度高度 高效，但是它们在实践中的有效性受到依从性差的限制，许多患者停止了 过早治疗和复发。该提议的目的是发展创新的长期表演 Naltrexone的皮下植入式，O'Neil长效纳曲酮植入物（Olani）， 迈向FDA批准。预计会产生纳曲酮血液水平足以阻止阿片类药物的作用 植入后6个月，奥拉尼规定了遵守每月注射XR-NTX的需求，并且 可以代表用于治疗Oud的医疗武术的重要新成员。 奥拉尼（Olani）一直在澳大利亚公司开发20年 在对照临床试验中评估并在澳大利亚使用临床使用的原型。当前公式具有 较高的药物负载和更好的释放曲线，并在GMP设施中制造。它已被使用 在800多名患者中，在临床上，人们相信该产品可以在美国成功开发。去 医疗和现任调查人员团队与FDA会面，以绘制通向新的发展道路 通过505 B（2）途径使用药物（NDA），并用Vivitrol作为比较产品。申请 FDA正在审查IND（＃134996）。该建议在UG3/UH3下寻求NIDA的支持 进行FDA建议对505 B（2）批准途径进行研究的机制。 在UG3阶段，研究1将在Minipig模型中评估Olani的局部组织毒性，并评估 研究2将生成健康受试者Olani的Pilot药代动力学（PK）数据，以确定功率 并最终确定样本量，以进行随后的生物等效性（BE）研究并支持可行性和耐受性。 如果在UG3阶段没有安全问题，纳曲酮的血液水平就足够了，则在UH3中 阶段（研究3）将在与NIDA和FDA协商后最终确定。研究3将比较6个月的PK Olani与XR-NTX作为纳曲酮血液中建立生物等效性（BE）的参考药物 OUD患者的水平，安全性和比较有效性。患者将被随机接受 3.6g剂量的Olani的单一皮下植入或重复剂量380 mg IM Q4 几周24周。参与者将在第6个月向Olani随机分配给Olani。 假设Olani将具有全身性暴露（CMAX，CMIN，AUC0-180）和NALTREXONE血液的MEC 与XR-NTX相当的水平。如果证明奥拉尼提供了一种安全，可行和有效的交付方法 在治疗水平的Naltrexone至少6个月，这将代表OUD领域的重大进展 治疗，为OUD患者提供有效的长期预防治疗。