NDA-Enabling Phase I Lofexidine Program

描述（由申请人提供）：（第一部分：描述）拟议的研究，“NDA-Enabling Phase I Lofexidine Program”，旨在表征盐酸Lofexidine的药代动力学和临床药理学特征，Lofexidine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。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)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)纳曲酮，(6)丁丙诺啡（可在临床环境中同时使用的相关适应症药物）之间的药物-药物药代动力学相互作用，(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、健康的志愿者或特殊人群中进行（如肝脏和肾脏损害研究的情况），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昔定母体分子。此外，在计划中的一项研究中，将使用放射性标记14c -洛非昔定的示踪剂量（约100 nCi）作为口服剂量，并通过加速质谱法分析，以跟踪母体药物的血浆和排泄药代动力学，并确定和量化洛非昔定的排泄代谢物。作为研究计划的一部分，建议制定14c -洛非昔定剂量和用于洛非昔定代谢物特异性鉴定和定量的适当的AMS方法，这将允许对血浆和尿液中的洛非昔定及其主要代谢物进行鉴定和定量。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。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，批准将允许第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): (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.