Drug-Drug Interactions Involving Methadone and Buprenorphine

涉及美沙酮和丁丙诺啡的药物相互作用

基本信息

批准号：
10649570
负责人：
Sean Hennessy
金额：
$ 45.94万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10649570
关键词：
ABCB1 gene Absence of pain sensation Accident and Emergency department Acute Address Adverse effects Age Area Biological Buprenorphine Case Series Central Nervous System Chronic Circulation Clinical Cytochrome P450 Dose Drug Combinations Drug Interactions Drug Kinetics Electrocardiogram Enzymes Ethnic Origin Etiology Exposure to Heart Arrest Heterogeneity Hospitalization Individual Investigation Knowledge Metabolism Methadone Methods Opioid Patients Persons Pharmaceutical Preparations Pharmacodynamics Pharmacoepidemiology Pharmacotherapy Physiological Poisoning Population Predisposition Property Public Health Race Relapse Research Screening Result Series Subgroup Therapeutic Time Transportation Work World Health clinically actionable cohort comorbidity comparative safety demographics design drug metabolism experience frailty genetic variant high throughput screening innovation insight knowledge base medication-assisted treatment multidisciplinary opioid epidemic opioid overdose opioid use disorder pharmacokinetic model pharmacokinetics and pharmacodynamics pharmacologic response screening sex treatment effect webinar

项目摘要

A crucial component of the US response to the opioid epidemic is expanding the use of medication assisted treatment, most commonly using methadone or buprenorphine, for opioid use disorder. Many persons with opioid use disorder have comorbidities that necessitate treatment with other acutely and chronically used medications, and this proportion is expected to rise with the evolving demographics of the opioid epidemic. Methadone and buprenorphine have pharmaco- kinetic and pharmacodynamic properties that make them highly likely to interact adversely with many other drugs, some of which are very commonly used. Further, past experience demonstrates that existing pharmacologic knowledge is insufficient to predict all clinically important drug-drug interactions. Despite the high potential for and serious consequences of both predicted and unanticipated drug-drug interactions, almost no research has examined the real-world health effects of drugs given concomitantly with methadone or buprenorphine. This presents a striking knowledge gap with large and growing clinical and public health consequences. This project's broad objective is to produce clinically-actionable and biologically-relevant knowledge about which medications interact with methadone and/or buprenorphine. Our work will further elucidate interactions with regard to order of drug initiation, dose-response effects, duration-response effects, and susceptible populations. We will achieve these objectives by: a) performing high-throughput physiologically-based pharmacokinetic screening to predict the degree to which two-drug and three-drug combinations that include methadone or buprenorphine increase biological exposure to those agents; b) performing high-throughput pharmacoepidemiologic screening of two-drug and three-drug combinations that include methadone or buprenorphine with regard to rate of emergency department presentation or hospitalization for opioid overdose and poisoning, opioid adverse effects, and cardiac arrest; c) convening an independent multidisciplinary Expert Panel to review screening results and prioritize potential drug interaction pairs and triads for further investigation; and d) conduct a series of rigorous pharmacoepidemiologic studies to inform causal inferences and thereby generate clinically-actionable evidence on prioritized methadone and buprenorphine drug-drug interactions. This rigorous, innovative study will produce actionable results that will guide the selection of drug therapy in the growing population of persons using methadone or buprenorphine who have comorbidities necessitating treatment.

美国应对阿片类药物流行病的一个重要组成部分是扩大药物辅助治疗的使用，最常见的是使用美沙酮或丁丙诺啡来治疗阿片类药物使用障碍。许多患有阿片类药物使用障碍的人需要使用其他急性和长期使用的药物治疗的合并症，这一比例是预计随着阿片类药物流行病人口结构的变化而增加。美沙酮和丁丙诺啡具有药物作用动力学和药效学特性使它们极有可能与许多其他药物产生不良相互作用，其中一些药物其中非常常用。此外，过去的经验表明，现有的药理学知识是不足以预测所有临床上重要的药物相互作用。尽管潜力巨大且严重由于预测和未预料到的药物相互作用的后果，几乎没有研究检验过现实世界与美沙酮或丁丙诺啡同时服用的药物对健康的影响。这呈现出惊人的知识差距具有巨大且不断增长的临床和公共卫生后果。该项目的广泛目标是产生临床上可操作的和生物学相关的知识药物与美沙酮和/或丁丙诺啡相互作用。我们的工作将进一步阐明以下方面的相互作用：药物起始顺序、剂量反应效应、持续时间反应效应和易感人群。我们将实现通过以下方式实现这些目标：a) 进行高通量基于生理学的药代动力学筛选以预测程度包含美沙酮或丁丙诺啡的两种药物和三种药物组合会增加生物暴露那些代理人； b) 对两种药物和三种药物组合进行高通量药物流行病学筛查其中包括美沙酮或丁丙诺啡与急诊科就诊或住院率的关系阿片类药物过量和中毒、阿片类药物不良反应和心脏骤停； c) 召集一个独立的多学科小组专家小组审查筛选结果并优先考虑潜在的药物相互作用对和三联体以供进一步调查； d) 进行一系列严格的药物流行病学研究，以提供因果推论，从而产生关于优先美沙酮和丁丙诺啡药物相互作用的临床可行证据。这种严谨、创新研究将产生可操作的结果，指导不断增长的人口中药物治疗的选择使用美沙酮或丁丙诺啡且患有需要治疗的合并症的人。