Evaluation of safety and pharmacokinetics of naltrexone implant

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问题 OUD和阿片类药物过量死亡。现有药物美沙酮， 丁丙诺啡和延长释放注射纳洛酮（XR-NTX;商品名：Vivitrol）是高度 有效，但它们在实践中的有效性受到依从性差的限制，许多患者停止使用 过早治疗和复发。该提案的目标是开发一种创新的长效 纳洛酮的皮下植入制剂，O 'Neil长效纳洛酮植入物（OLANI）， FDA的批准。预期产生足以阻断阿片类药物作用的纳洛酮血液水平 在植入后的6个月内，OLANI避免了每月注射XR-NTX的需要， 可以代表治疗OUD的医疗设备的重要新添加。 OLANI由澳大利亚Go Medical公司开发了20年， 原型在对照临床试验中进行了评估，并在澳大利亚临床使用。目前的提法有 更高的药物负载和更好的释放曲线，并在GMP设施中制造。它已被用于 在临床上超过800名患者，给予信心，该产品可以在美国成功开发。去 医疗和目前的研究小组会见了FDA，以制定一条新的发展道路。 通过505 B（2）途径进行药物申请（NDA），Vivitrol作为对照产品。的申请 IND（# 134996）正在接受FDA的审查。该提案寻求UG 3/UH 3下NIDA的支持 进行FDA推荐的505 B（2）批准途径研究的机制。 在UG 3阶段，研究1将在小型猪模型中评价OLANI的局部组织毒性， 研究2将生成健康受试者中OLANI的初步药代动力学（PK）数据，以确定把握度 并最终确定后续生物等效性（BE）研究的样本量，以支持可行性和耐受性。 如果在UG 3阶段没有安全性问题并且纳洛酮血液水平足够，那么在UH 3阶段， 第三阶段（研究3）将在与NIDA和FDA协商后完成。研究3将比较以下药物的6个月PK： OLANI与XR-NTX作为参比药物，以确定纳洛酮血液方面的生物等效性（BE） 水平、安全性和有效性比较。患者将随机接受 单次皮下植入3.6g剂量的OLANI或重复剂量的Vivitrol 380 mg IM q4 24个星期。随机分配至OLANI组的受试者将在第6个月时获得额外的植入物。我们 假设OLANI将具有纳洛酮血液的全身暴露量（Cmax、Cmin、AUC 0 -180）和MEC 水平与XR-NTX相当。如果OLANI被证明是一种安全、可行和有效的分娩方法， 在治疗水平的纳洛酮至少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复发预防治疗。

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.