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

描述(由申请者提供)：这个以患者为导向的研究职业发展奖(K23)项目的目的是促进Gavin Bart博士发展成为一名独立的多学科转化型内科医生兼科学家，专注于影响物质使用障碍治疗结果的生物因素。特别是在实验和临床药理学以及人群药代动力学方面的教学和研究培训，将为持续的研究生涯提供必要的技能，评估用于治疗成瘾性疾病的疗法，目前全世界死于成瘾性疾病的12.4%。本项目将以苗族人为重点，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，苗族人在美沙酮剂量显著低于我们的非苗族人的情况下有更好的治疗结果(即，尿毒学阳性结果保留1年并减少)。我们假设，这种非常成功的美沙酮治疗结果与更大的美沙酮暴露相关，以毫克/公斤为基础，以曲线下面积衡量。具体目的是用群体药代动力学方法比较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的ADC值相关联。保存下来的DNA数据库也将用于未来的药物遗传学研究。苗族是一个与老挝山区不同的种族群体。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名苗族人登记在亨内平县医疗中心成瘾药物计划美沙酮诊所；这使这成为世界上最大的美沙酮维持苗族人口。因为苗族人代表着一个遗传隔离的种群，几乎没有混合物质，他们为药代动力学和药物遗传学研究提供了一个相关和理想的机会。研究美沙酮在苗族和非苗族人群中的药代动力学，可能提供新的治疗策略，可推广到非苗族美沙酮人群。从CDA学到的技能可以应用于其他特殊人群的治疗结果研究，或用于(或用于开发)其他成瘾性疾病的药物的研究。

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.