Methadone population pharmacokinetics: treatment outcome in Hmong and non-Hmong

描述（由申请人提供）：这个以指导患者为导向的研究职业发展奖（K23）项目的目的是培养Gavin Bart博士成为一个独立的多学科转化医师-科学家，专注于影响物质使用障碍治疗结果的生物学因素。特别是在实验和临床药理学和人口药代动力学方面的教学和研究培训，将为持续的研究职业提供必要的技能，以评估用于治疗成瘾疾病的治疗方法，这些疾病目前占全世界死亡人数的12.4%。本项目将把苗族作为美沙酮维持药代动力学研究的模型人群。我们之前观察到，苗族患者使用较低剂量的美沙酮比非苗族患者有更好的治疗效果（即1年的保留率和尿毒理学阳性结果的减少）。我们假设这种高度成功的美沙酮治疗结果，与以毫克/千克为基础的更大的美沙酮暴露有关，以曲线下面积来衡量。具体目的是利用群体药代动力学比较苗族和美沙酮在苗族和非苗族的药代动力学，并将治疗结果与美沙酮ADC联系起来。保存的DMA库也将用于未来的药物遗传学研究。苗族是老挝山区的一个独特的民族。几个世纪以来，苗族人一直种植罂粟，估计有7%-12%的鸦片种植者依赖鸦片。自20世纪70年代以来，已有7万苗族移民到明尼苏达州。其中200名苗族人在亨内平县医疗中心成瘾药物项目美沙酮诊所注册；使其成为世界上美沙酮维持的苗族人口最多的地方。由于苗族是一个遗传上孤立的群体，几乎没有混合，他们为药代动力学和药物遗传学研究提供了一个相关的和理想的机会。研究苗族与非苗族美沙酮的药代动力学，可以为非苗族美沙酮人群提供新的治疗策略。从该CDA中学到的技能可用于研究其他特殊人群的治疗结果，或用于（或正在开发）治疗其他成瘾性疾病的药物。

DESCRIPTION (provided by applicant): The purpose of this Mentored Patient-Oriented Research Career Development Award (K23) project is to foster the development of Dr. Gavin Bart into an independent multidisciplinary translational physician-scientist focusing on the biological factors that influence substance use disorder treatment outcome. Didactic and research training in experimental and clinical pharmacology and population pharmacokinetics, in particular, will provide skills necessary for a sustained research career evaluating therapeutics used to treat the addictive diseases, which currently account for 12.4% of deaths worldwide. This project will focus on the Hmong as 'a model population for pharmacokinetic research of methadone maintenance. We previously observed that the Hmong have superior treatment outcome (i.e., 1-year retention and reduction in urine toxicology positive results) on significantly lower doses of methadone than our non-Hmong population. We hypothesize that this highly successful methadone treatment outcome, is correlated to greater methadone exposure on a milligram/kilogram basis, measured as area under the curve. The specific aims are to compare the pharmacokinetics of methadone in Hmong to non-Hmong using population pharmacokinetics and to correlate treatment outcome to methadone ADC. A bank of preserved DMA will be also obtained for future pharmacogenetic studies. The Hmong are an ethnically distinct group from the mountains of Laos. For centuries the Hmong have cultivated opium poppies and an estimated 7%-12% of opium farmers are opiate dependent. Since the 1970s, 70,000 Hmong have immigrated to Minnesota. Two hundred of these Hmong are enrolled in the Hennepin County Medical Center Addiction Medicine Program methadone clinic; making this the largest methadone maintained Hmong population in the world. Because the Hmong represent a genetically isolated population with little admixture, they provide a relevant and ideal opportunity for pharmacokinetic and pharmacogenetic research. Investigation of the pharmacokinetics of methadone in the Hmong compared to non-Hmong may inform new treatment strategies that could be generalized to non-Hmong methadone populations. The skills learned from this CDA could be applied to studies of treatment outcome in other special populations or for medications used (or in development) for other addictive diseases.