NDA-Enabling Phase I Lofexidine Program

NDA 启动 I 期洛非西丁项目

• 批准号: 8488001
• 负责人: Charles W. Gorodetzky
• 金额: $ 46.85万
• 依托单位: US WORLDMEDS, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8488001
• 关键词: Acute; Adrenergic Agonists; Age; Analgesics; Applications Grants; Area; Biological Availability; Body mass index; Buprenorphine; Clinical; Clinical Pharmacology; Development; Dose; Drug Kinetics; Drug Metabolic Detoxication; End stage renal failure; Equilibrium; Evaluation; Excretory function; FDA approved; Fasting; Fatty acid glycerol esters; Food; Hepatic; Heroin; Hydrochloride Salt; Impairment; Intravenous; Investigational Drugs; Kidney; Label; Liquid Chromatography; Literature; Marketing; Mass Spectrum Analysis; Medical; Methadone; Methodology; Methods; Naltrexone; Opiate Addiction; Opiates; Opioid; Oral; Oxycodone; Parents; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Plasma; Population; Product Labeling; Property; Radio; Radiolabeled; Recovery; Relative (related person); Renal function; Reporting; Research; Rural; Safety; Staging; Tablets; Time; Tracer; United Kingdom; United States Food and Drug Administration; United States National Institutes of Health; United States Substance Abuse and Mental Health Services Administration; Urine; Withdrawal; Work; base; healthy volunteer; intravenous administration; liquid chromatography mass spectrometry; liver function; lofexidine; meetings; named group; opioid abuse; opioid withdrawal; phase 3 study; prescription opiate; programs; radiotracer; sex; suburb; tandem mass spectrometry; therapy development; volunteer

DESCRIPTION (provided by applicant): (Part 1: Description) the proposed research, "NDA-Enabling Phase I Lofexidine Program," is aimed at characterizing the pharmacokinetic and clinical pharmacological profiles of lofexidine hydrochloride, an alpha-2 adrenergic agonist under development for the treatment of acute withdrawal from short acting opioids. The research program consists of seven studies, each with a particular objective that will add to the overall understanding of the pharmacology of the investigational drug. The studies include evaluation of (1) effect of food on lofexidine's bioavailability, (2) pharmacokinetics in hepatically-impaired patients, (3) pharmacokinetics in renally-impaired patients, drug-drug pharmacokinetic interactions between lofexidine and (4) methadone, (5) naltrexone, and (6) buprenorphine (drugs for related indications that may be used concurrently in a clinical setting), and (7) a study of absolute bioavailability and mass balance of lofexidine. The studies will be conducted in normal, healthy volunteers or special populations (as in the case of the hepatic and renal impairment studies) and will employ use of liquid chromatography tandem mass spectrometry (LC/MS/MS) methodology to detect lofexidine hydrochloride parent molecule in the urine and plasma. Additionally, for one of the planned studies, tracer amounts (approximately 100 nCi) of radio-labeled 14C-lofexidine will be used in an oral dose and analyzed by Accelerated Mass Spectrometry in order to follow the plasma and excretion pharmacokinetics of parent drug, and to identify and quantify the excreted metabolites of lofexidine. The 14C-lofexidine dose and the appropriate AMS methods for specific identification and quantification of lofexidine metabolites is proposed to be developed as part of the research plan, which will allow identification and quantification of both lofexidine and its major metabolites in the plasma and urine. Quantification of lofexidine and/or its major metabolites over time in addition to observed tolerance and evaluation of other clinical parameters in each of the planned studies will add to the overall understanding of the pharmacokinetics and pharmacodynamics of lofexidine in the body. This information is needed to allow appropriate labeling of the product for its entrance to the US market. Furthermore, the planned research has been defined by the FDA as critical to complete the clinical pharmacology section requirements for a New Drug Application for lofexidine hydrochloride, approval of which will allow entrance of the first non-narcotic, non-addictive drug indicated for the treatment of opiate withdrawal to the US market.

描述（由申请人提供）：（第1部分：描述）拟议研究“NDA启用I期洛非西定项目”旨在表征盐酸洛非西定的药代动力学和临床药理学特征，盐酸洛非西定是一种正在开发的α-2肾上腺素能激动剂，用于治疗短效阿片类药物急性戒断。该研究项目包括7项研究，每项研究都有一个特定的目的，这将增加对研究药物药理学的整体理解。研究包括评价（1）食物对洛非西定生物利用度的影响，（2）肝损害患者的药代动力学，（3）肾损害患者的药代动力学，洛非西定与（4）美沙酮、（5）纳洛酮和（6）丁丙诺啡之间的药物-药物药代动力学相互作用（可在临床环境中同时使用的用于相关适应症的药物），和（7）洛非西定的绝对生物利用度和质量平衡的研究。研究将在正常健康志愿者或特殊人群（如肝肾损害研究）中进行，并将采用液相色谱串联质谱（LC/MS/MS）方法检测尿液和血浆中的盐酸洛非西定母体分子。此外，对于其中一项计划的研究，将在口服剂量中使用示踪量（约100 nCi）的放射性标记14 C-洛非西定，并通过加速质谱法进行分析，以跟踪母体药物的血浆和排泄药代动力学，并鉴别和定量洛非西定的排泄代谢产物。作为研究计划的一部分，拟开发14 C-洛非西定剂量和用于洛非西定代谢物特异性鉴别和定量的适当AMS方法，以鉴别和定量血浆和尿液中的洛非西定及其主要代谢物。在每项计划的研究中，除了观察到的耐受性和其他临床参数的评价外，洛非西定和/或其主要代谢产物随时间的定量将增加对洛非西定在体内的药代动力学和药效学的总体理解。需要这些信息，以便为进入美国市场的产品贴上适当的标签。此外，FDA将计划中的研究定义为对于完成盐酸洛非西定新药申请的临床药理学部分要求至关重要，该申请的批准将允许第一种用于治疗阿片类药物的非麻醉性、非成瘾性药物进入美国市场。