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问题 美国的阿片类药物过量死亡和 OUD 疾病。目前可用的药物有美沙酮、 丁丙诺啡和缓释注射纳曲酮（XR-NTX；商品名：Vivitrol）具有高度 有效，但其在实践中的有效性因依从性差而受到限制，许多患者停止了治疗 治疗过早，容易复发。该提案的目标是开发一种创新的长效药物 纳曲酮皮下植入制剂，奥尼尔长效纳曲酮植入剂（OLANI）， 争取 FDA 批准。预计产生的纳曲酮血液浓度足以阻止阿片类药物的作用 植入后 6 个月内，OLANI 无需坚持每月注射 XR-NTX，并且 可能是治疗 OUD 的医疗设备的重要新补充。 OLANI 由一家澳大利亚公司 Go Medical 开发了 20 年，并与多家公司合作 原型在对照临床试验中进行评估并在澳大利亚临床使用。目前的配方有 更高的载药量和更好的释放曲线，并在 GMP 设施中生产。已被使用 已在 800 多名患者中进行临床试验，这让人们对该产品能够在美国成功开发充满信心。去 医疗和当前的研究团队与 FDA 会面，制定了新的开发路径 以 Vivitrol 作为比较产品，通过 505 b(2) 途径进行药物申请 (NDA)。申请 IND (# 134996) 正在接受 FDA 审查。该提案寻求 NIDA 在 UG3/UH3 下的支持 机制来进行 FDA 推荐的 505 b(2) 批准途径的研究。 在 UG3 阶段，研究 1 将评估 OLANI 在小型猪模型中的局部组织毒性，以及 研究 2 将生成 OLANI 在健康受试者中的初步药代动力学 (PK) 数据，以确定功效 并最终确定后续生物等效性 (BE) 研究的样本量，并支持可行性和耐受性。 如果没有安全问题并且纳曲酮血液水平在 UG3 阶段足够，那么在 UH3 阶段 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 作为参考药物，建立纳曲酮血液的生物等效性 (BE) OUD 患者的水平、安全性和比较有效性。患者将被随机分配接受 单次皮下植入 3.6g 剂量的 OLANI 或重复剂量 Vivitrol 380 mg IM q4 周 24 周。随机分配至 OLANI 的参与者将在第 6 个月获得额外的植入物。我们 假设 OLANI 将有纳曲酮血液的全身暴露 (Cmax,Cmin,AUC0-180) 和 MEC 水平与 XR-NTX 相当。如果 OLANI 被证明可以提供安全、可行且有效的分娩方法 如果纳曲酮在治疗水平上持续至少 6 个月，这将代表 OUD 领域的重大进步 治疗，为 OUD 患者提供有效的长期复发预防治疗。