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 期洛非西定计划”旨在表征盐酸洛非西定的药代动力学和临床药理学特征，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的急性戒断。该研究计划由七项研究组成，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了解。这些研究包括评估（1）食物对洛非西定生物利用度的影响，（2）肝功能不全患者的药代动力学，（3）肾功能不全患者的药代动力学，洛非西定与（4）美沙酮，（5）纳曲酮和（6）丁丙诺啡（可在临床环境中同时使用的相关适应症的药物）之间的药物-药物药代动力学相互作用，以及(7)洛非西定绝对生物利用度和质量平衡的研究。这些研究将在正常、健康志愿者或特殊人群（如肝肾损伤研究的情况下）中进行，并将采用液相色谱串联质谱（LC/MS/MS）方法来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放射性标记的 14C-洛非西定的示踪剂量（约 100 nCi）并通过加速质谱法进行分析，以跟踪母药的血浆和排泄药代动力学，并识别和量化洛非西定的排泄代谢物。作为研究计划的一部分，建议开发 14C-洛非西定剂量和适当的 AMS 方法来具体识别和定量洛非西定代谢物，这将允许识别和定量血浆和尿液中的洛非西定及其主要代谢物。除了在每项计划研究中观察到的耐受性和其他临床参数的评估之外，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对洛非西定在体内的药代动力学和药效学的整体了解。需要此信息才能对产品进入美国市场进行适当的标记。此外，FDA已将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个用于治疗阿片戒断的非麻醉、非成瘾药物进入美国市场。

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.