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: 10580003
• 负责人: ADAM BISAGA
• 金额: $ 386.45万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580003
• 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; Phase; Placebos; Randomized; Recommendation; Recovery; Relapse; Research Personnel; Risk Reduction; Safety; Saline; Sample Size; Surgical Replantation; Testing; Therapeutic; Therapeutic Equivalency; Time; Tissues; Toxic effect; arm; comparative effectiveness; design; healthy volunteer; implantation; individual variation; innovation; manufacture; novel therapeutics; opioid epidemic; opioid mortality; opioid use disorder; opioid withdrawal; overdose prevention; patient engagement; pharmacologic; premature; prototype; psychosocial; relapse prevention; 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