Drug-Drug Interactions Involving Methadone and Buprenorphine

涉及美沙酮和丁丙诺啡的药物相互作用

• 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
• 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

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的一个关键组成部分是扩大药物辅助治疗的使用， 最常使用美沙酮或丁丙诺啡，用于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慢性药物治疗的合并症，这一比例是 预计将随着阿片类药物流行的人口统计学变化而上升。美沙酮和丁丙诺啡具有药理学- 动力学和药效学特性使它们很可能与许多其他药物发生不利的相互作用， 这些都是非常常用的。此外，过去的经验表明，现有的药理学知识 不足以预测所有临床上重要的药物相互作用。尽管有很高的潜力和严重的 预测和非预期的药物相互作用的后果，几乎没有研究已经检查了现实世界 与美沙酮或丁丙诺啡同时服用药物对健康的影响。这显示了一个惊人的知识差距 并对临床和公共卫生产生了越来越大的影响。 该项目的广泛目标是产生临床可操作和生物相关的知识， 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关于 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 a）进行基于生理学的高通量药代动力学筛选以预测 包括美沙酮或丁丙诺啡的两种药物和三种药物组合增加了生物暴露， 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选 包括美沙酮或丁丙诺啡， 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专家小组， 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合会作进一步调查; 和d）进行一系列严格的药物流行病学研究，以提供因果推断，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操作证据。这种严谨， 创新的研究将产生可操作的结果，这将指导药物治疗的选择，在不断增长的人口 使用美沙酮或丁丙诺啡的患有需要治疗的合并症的人。