NDA-Enabling Phase I Lofexidine Program

描述(申请人提供)：拟议的研究旨在描述盐酸洛非西定的药代动力学、药效学和临床药理学特征，盐酸洛非西定是一种正在开发中的α-2肾上腺素能激动剂，用于治疗短效阿片类药物的急性戒断。应用程序的修订扩大了原计划的两项药物-药物相互作用研究的范围，并增加了整个计划的密集心电监测和集中分析。该研究计划包括七项研究，每项研究都有一个特定的目标，将增加对研究药物的药理学的总体了解。这些研究包括：(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隔相互作用，(5)洛非西定和纳曲酮(美沙酮、丁丙诺啡和纳曲酮是临床上可能同时使用的相关适应症药物)的药物-药物动力学相互作用，(6)洛非西定在肾损害患者中的药代动力学，以及(7)洛非西定在心脏损害患者中的药代动力学。这些研究将在正常、健康的志愿者或特殊人群中进行(例如肝脏和肾脏损害研究以及美沙酮/丁丙诺啡相互作用研究)，并采用适当的方法评估尿液和血浆中洛非西定和相关化合物的水平。每项研究都将使用动态心电图监测，以确保通过专门的核心实验室进行高质量的心电记录和集中分析。在每一项计划的研究中，除了观察到的耐受性和其他临床参数的评估外，随着时间的推移对洛非西定和/或其主要代谢物进行量化，将有助于全面了解洛非西定在体内的药代动力学和药效学。这一修订申请侧重于上述研究3和4的变化，以及在整个计划中增加了密集的心电监测。这些信息是必要的，以便为进入美国市场的产品适当贴上标签。此外，FDA将这项计划中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也是唯一一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。

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.