NDA-Enabling Phase I Lofexidine Program

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已将计划的研究定义为完成盐酸洛非西定新药申请的临床药理学部分要求的关键，该申请的批准将允许第一种用于治疗阿片类药物戒断的非麻醉性、非成瘾性药物进入美国市场。 公共卫生相关性：（项目摘要，第2部分：阿片类药物滥用和依赖在美国是一个严重且日益严重的问题，估计有520万非医疗相关的处方阿片类止痛药使用者，如Lortab（R）和OxyContin（R）（SAMHSA，2008年），美国有100万海洛因成瘾者（美国国立卫生研究院，2006年），最近的文章表明，虐待正在蔓延到农村和郊区（Archibold，2009年）。阿片类药物依赖人群的医疗需求未得到满足，目前只有两种FDA批准的药物（美沙酮和丁丙诺啡）可用于治疗阿片类药物戒断。两者都是阿片类药物，有效地作为替代或替代疗法，有滥用的可能性，本身是受管制的物质。FDA批准盐酸洛非西定将使第一个非麻醉性，非成瘾性产品进入市场，用于治疗阿片类药物戒断，这是从阿片类药物依赖中恢复的第一个障碍。计划中的研究需要了解洛非西定在体内的作用方式，以便评估适当的剂量、膳食要求、与其他治疗药物联合使用的安全性以及肝肾功能较差患者的安全性考虑因素。

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. PUBLIC HEALTH RELEVANCE: (Project Summary, Part 2: Relevance) Opioid abuse and dependence is a serious and growing problem in the US, with an estimated 5.2 million nonmedical-related users of prescription opiate pain killers such as Lortab(R) and OxyContin(R) (SAMHSA, 2008), 1 million heroin addicts in the US (National Institutes of Health, 2006), and recent articles suggesting that abuse is spreading into rural and suburban areas (Archibold, 2009). There is an unmet medical need in the opioid-dependent population, with only two FDA-approved drugs (methadone and buprenorphine) currently available to treat opioid withdrawal. Both are opiate products that effectively operate as replacement or substitution therapies, have abuse potential and are themselves controlled substances. FDA approval of lofexidine hydrochloride will enable the entrance of the first non-narcotic, non-addictive product to the market for the treatment of opioid withdrawal, the first hurdle in recovery from opioid dependence. The planned research is required to understand how lofexidine works in the body so that appropriate dosing, meal requirements, the safety of combination with other treatment drugs, and safety considerations for patients with poor liver and kidney functions can be evaluated.