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.

项目摘要/摘要 癫痫病影响了全球超过7000万人，其中估计在美国有340万人。多个广泛 用过的抗癫痫药（AED）具有脱靶效应诱导的关键药物代谢酶，产生 许多潜在的药物相互作用（DDIS）。一种与现实世界特别高的互动 相关性但最少的临床证据已据称是在这些酶诱导的AED之间发生的 （EI-AEDS）和直接作用口服抗凝剂（DOAC）。用抗凝剂的AED共同处方是 由于癫痫与DOAC的主要适应症之间的频繁并发和因果关系，因此很常见。 EI-AED诱导DOAC抽象和代谢的两个关键组成部分，这可能导致较低 潜在的亚治疗，DOAC的水平以及血栓事件的风险增加。证据 这些DDI主要由体外和动物数据组成。现有的人类研究有限 由于两者的适用性：发现的实质性不一致，以及使研究处于高风险的方法 出于偏见和混淆。此外，这些人类研究的狭窄关注对成对的EI-AED/DOAC相互作用 忽略高阶药物毒品相互作用（3DIS）的潜在作用，特别是考虑到高 癫痫种群中多药的患病率。该研究计划的目的是在方法论上应用 严格的设计并利用大规模的行政索赔数据来解决有关真实的知识差距 与EI-AED和伴随的药物相互作用相关的世界DOAC热失败。在AIM 1中，我们将 使用回顾性事件用户队列设计比较成人癫痫的血栓栓塞事件率 与EI-AEDS相比，暴露于DOAC与活跃的比较器组暴露于非酶的DOAC 诱导AED（NEI-AEDS）。鉴于利用率和血小板风险的关键差异，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 对观察和未观察的混杂因素（通过代理调整），数据自适应的估计值 高维倾向评分将被雇用。在AIM 2中，我们将使用案例交叉设计来探索 3DI在患有癫痫处开处方的EI-AED和DOAC的成年人中的血栓性事件中的作用。一本小说 - 根据伴随药物的临时关联，将进行3DI筛查的人方法 与血栓栓塞事件。将估计值与规定的否定案例组相比 具有DOAC的AED，以减轻伴随药物的直接影响和混淆，以及 将3DI与DDI信号区分开。总体而言，这项研究将有助于开处方的进步 癫痫患者的标准需要抗凝并为将来的3I调查提供基准。 从这项精神引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 申请人建立持续的博士后研究计划的基础，并朝着职业发展 作为专门研究神经性电子学和药物电子学的独立研究员。