Interactions of Enzyme-Inducing Antiepileptic Drugs with Direct-Acting Oral Anticoagulants: Risk of Thromboembolic Events

酶诱导抗癫痫药物与直接作用口服抗凝剂的相互作用：血栓栓塞事件的风险

• 批准号: 10605482
• 负责人: Emily Kate Acton
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-03 至 2025-02-02
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605482
• 关键词: Address; Adult; Affect; Animal Experimentation; Anticoagulants; Anticoagulation; Antiepileptic Agents; Atrial Fibrillation; Benchmarking; Biological; CYP3A4 gene; Carrier Proteins; Case Study; Clinical; Crossover Design; Data; Data Set; Databases; Disease; Drug Interactions; Drug Kinetics; Drug Prescriptions; Enzyme Induction; Enzyme Interaction; Enzymes; Epilepsy; Event; Exposure to; Failure; Foundations; Future; Glycoproteins; Goals; Graph; Hemorrhage; High Prevalence; Human; In Vitro; Incidence; Individual; Intestinal Absorption; Investigation; Kidney; Knowledge; Link; Medical; Mentors; Metabolism; Methodology; Methods; Nature; Neuroepidemiology; Observational Study; Oral; Outcome; Patients; Permeability; Persons; Pharmaceutical Preparations; Pharmacoepidemiology; Polypharmacy; Population; Postdoctoral Fellow; Practice Guidelines; Prevalence; Proxy; Pulmonary Embolism; Reporting; Research; Research Personnel; Risk; Role; Series; Signal Transduction; Therapeutic; Thrombus; Training; absorption; active comparator; animal data; career; clinical risk; cohort; comparative safety; comparison group; complex data; deep vein; design; experience; experimental study; health care service utilization; high dimensionality; high risk; improved; nervous system disorder; novel; screening; skills; therapeutic effectiveness; thrombotic

Project Summary/Abstract Epilepsy affects over 70 million people worldwide, including an estimated 3.4 million in the US. Multiple widely- used antiepileptic drugs (AEDs) have off-target effects inducing key drug metabolizing enzymes, yielding numerous potential drug-drug interactions (DDIs). One such interaction with particularly high real-world relevance, but minimal clinical evidence, has been purported to occur between these enzyme-inducing AEDs (EI-AEDs) and direct-acting oral anticoagulants (DOACs). Co-prescription of AEDs with anticoagulants is common due to the frequent concurrency and causal links between epilepsy and the main indications for DOACs. EI-AEDs induce two crucial components of DOAC absorption and metabolism, which may lead to lower, potentially sub-therapeutic, levels of DOACs, and an increased risk of thromboembolic events. Evidence for these DDIs is composed primarily of in vitro and animal data. Existing human studies have limited real-world applicability due to both: substantial inconsistencies in findings, and methods that put the research at high risk for bias and confounding. Further, these human studies’ narrow focus on pairwise EI-AED/DOAC interactions disregards the potential role of higher-order drug-drug-drug interactions (3DIs), particularly given the high prevalence of polypharmacy in epilepsy populations. The goal of this research plan is to apply methodologically rigorous designs and leverage large-scale administrative claims data to address knowledge gaps regarding real- world DOAC therapeutic failures associated with EI-AED and concomitant drug interactions. In Aim 1, we will use a retrospective incident user cohort design to compare thromboembolic event rates in adults with epilepsy exposed to DOACs with EI-AEDs versus an active comparator group exposed to DOACs with non-enzyme inducing AEDs (NEI-AEDs). Given critical differences in utilization and thrombotic risk, we will separately analyze DOAC use for atrial fibrillation (1A) and deep vein thrombus/pulmonary embolism (1B). To generate effect estimates with vigorous control for observed and unobserved confounders (via proxy-adjustment), data-adaptive high-dimensional propensity scoring will be employed. In Aim 2, we will use a case-crossover design to explore the role of 3DIs in thromboembolic events in adults with epilepsy prescribed EI-AEDs and DOACs. A novel within- person approach to 3DI screening will be undertaken based on the temporal associations of concomitant drugs with thromboembolic events. Estimates will be quantitatively compared to a negative case group prescribed NEI- AEDs with DOACs in order to mitigate the direct effects and confounding by concomitant drugs, as well as to differentiate 3DI from DDI signals. Overall, this research will contribute to the advancement of prescribing standards for epilepsy patients requiring anticoagulation and provide benchmarks for future 3DI investigations. The valuable skills and experiences gained from this mentor-guided research and training will serve as essential foundations for the applicant to build continued postdoctoral research initiatives, and to advance towards a career as an independent investigator-clinician specializing in neuroepidemiology and pharmacoepidemiology.

项目总结/摘要 癫痫影响着全世界超过7000万人，其中估计有340万人在美国。多个广泛- 使用的抗癫痫药物（AED）具有脱靶效应，诱导关键药物代谢酶， 许多潜在的药物相互作用（DDI）。一个这样的互动与特别高的现实世界 相关性，但最小的临床证据，已被认为是发生在这些酶诱导AED之间 （EI-AED）和直接作用口服抗凝剂（DOAC）。抗癫痫药物与抗凝剂的联合处方 由于癫痫与DOAC的主要适应症之间的频繁并发性和因果关系，因此很常见。 EI-AED诱导DOAC吸收和代谢的两个关键组分，这可能导致较低的， 潜在的亚治疗、DOAC水平和血栓栓塞事件风险增加。证据 这些DDI主要由体外和动物数据组成。现有的人类研究限制了现实世界 适用性，由于这两个：大量的不一致的结果，和方法，使研究处于高风险 偏见和混淆。此外，这些人类研究的狭隘重点是成对EI-AED/DOAC相互作用 忽略了高阶药物-药物-药物相互作用（3DI）的潜在作用，特别是考虑到高 癫痫人群中多种药物的患病率。本研究计划的目标是在方法论上应用 严格的设计和利用大规模的行政索赔数据，以解决知识差距，关于真实的- 与EI-AED和伴随药物相互作用相关的世界DOAC治疗失败。在目标1中，我们 使用回顾性事件用户队列设计，比较癫痫成人的血栓栓塞事件发生率 暴露于含EI-AED的DOAC与暴露于含非酶的DOAC的活性对照组 诱导抗癫痫药物（NEI-AEDs）。考虑到利用率和血栓形成风险的关键差异，我们将分别分析 DOAC用于房颤（1A）和深静脉血栓/肺栓塞（1B）。产生效果 对观察到的和未观察到的混杂因素进行严格控制的估计（通过代理调整），数据自适应 将采用高维倾向评分。在目标2中，我们将使用病例交叉设计来探索 3DI在EI-AED和DOAC处方癫痫成人血栓栓塞事件中的作用。一部小说在- 将根据伴随药物的时间相关性进行3DI筛选的个人方法 血栓栓塞事件。将估计值与NEI规定的阴性病例组进行定量比较- AED与DOAC联合使用，以减轻直接效应和伴随药物的混淆，以及 区分3DI和DDI信号。总的来说，这项研究将有助于处方的进步 需要抗凝治疗的癫痫患者的标准，并为未来的3DI研究提供基准。 从这一导师指导的研究和培训中获得的宝贵技能和经验将是必不可少的 为申请人建立持续的博士后研究计划奠定基础，并推进职业生涯 作为一名独立的神经流行病学和药物流行病学专家。