NDA-Enabling Phase I Lofexidine Program

描述（由申请人提供）：拟议的研究旨在描述盐酸洛非昔定的药代动力学、药效学和临床药理学特征，洛非昔定是一种正在开发的用于治疗短效阿片类药物急性戒断的α -2肾上腺素能激动剂。申请修订需要增加两个原计划的药物-药物相互作用研究的范围，并为整个项目增加密集的ECG监测和集中分析。该研究项目包括7项研究，每项研究都有一个特定的目标，将增加对研究药物药理学的整体理解。这些研究包括评价(1)洛非西定的绝对生物利用度和质量平衡，(2)食物对洛非西定生物利用度的影响，（3和4）药物-药物药效学相互作用，重点是洛非西定与美沙酮或丁丙诺啡之间的心脏间期相互作用，(5)洛非西定与纳曲酮的药物-药物药代动力学相互作用（美沙酮、丁丙诺啡和纳曲酮是相关适应症的药物，可以在临床环境中同时使用）。(6)洛非昔定在肾损害患者体内的药代动力学；(7)洛非昔定在肝损害患者体内的药代动力学。这些研究将在正常、健康的志愿者或特殊人群中进行（如肝肾损害研究和美沙酮/丁丙诺啡相互作用研究），并采用适当的方法评估尿和血浆中洛非昔定及相关化合物的水平。每项研究都将使用动态心电图监测，以确保高质量的心电图记录和通过专门的核心实验室进行集中分析。在每一项计划中的研究中，对洛非昔定和/或其主要代谢物随时间的量化，以及观察到的耐受性和对其他临床参数的评估，将有助于全面了解洛非昔定在体内的药代动力学和药效学。此修订应用程序侧重于上述研究3和4的变化以及在整个程序中增加强化ECG监测。这些信息对于产品进入美国市场的适当标签是必需的。此外，计划中的研究已被FDA定义为完成盐酸洛非昔定新药申请的临床药理学部分要求的关键，该批准将允许第一种也是唯一一种用于治疗阿片类戒断的非麻醉性、非成瘾性药物进入美国市场。

DESCRIPTION (provided by applicant): The proposed research is aimed at characterizing the pharmacokinetic, pharmacodynamics, 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 application revision entails an increased scope for two of the originally planned drug-drug interaction studies and adding intensive ECG monitoring and centralized analysis for the entire program. 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) absolute bioavailability and mass balance of lofexidine, (2) effect of food on lofexidine's bioavailability, (3 and 4) drug-drug pharmacodynamic interaction with a focus on heart interval interaction effects between lofexidine and methadone or buprenorphine, (5) drug-drug pharmacokinetic interaction of lofexidine and naltrexone (methadone, buprenorphine and naltrexone are drugs for related indications that may be used concurrently in a clinical setting), (6) pharmacokinetics of lofexidine in renally-impaired patients, and (7) pharmacokinetics of lofexidine in hepatically-impaired patients. The studies will be conducted in normal, healthy volunteers or special populations (as in the case of the hepatic and renal impairment studies and methadone/buprenorphine interaction studies) and employ appropriate methodology to evaluate levels of lofexidine and related compounds in urine and plasma. Holter monitoring will be used in each study to ensure quality ECG recording and centralized analysis through a specialized core lab. 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 revision application focuses on the change in studies 3 and 4 noted above and the addition of intensive ECG monitoring across the program. 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 and only non-narcotic, non-addictive drug indicated for the treatment of opiate withdrawal to the US market.