NDA-Enabling Phase I Lofexidine Program

描述（由申请方提供）：拟定研究旨在表征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。申请修订需要增加两项原计划的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的，这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）洛非西定与纳洛酮的药物-药物药代动力学相互作用（美沙酮、丁丙诺啡和纳洛酮是用于相关适应症的药物，可以在临床环境中同时使用），（6）洛非西定在肾损害患者中的药代动力学，和（7）洛非西定在肝损害患者中的药代动力学。研究将在正常健康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价尿液和血浆中洛非西定和相关化合物的水平。每项研究将使用霍尔特监测，以确保通过专业核心实验室进行高质量的ECG记录和集中分析。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。本修订申请重点关注上述研究3和4的变更以及在整个项目中增加强化ECG监测。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.