Clinical Importance of Drug-Drug Interactions

项目摘要 药物间相互作用（DDI）不仅是药物流行病学家和临床医学家的研究课题， 药理学家，但作为一个重要的问题，公共卫生，特别是在老年人面临着多种 慢性病已知的DDI导致了13%的药物不良事件和4.8%的医院不良事件。 老年人的入学率。即使是这些高数字也可能低估了DDI的真实影响，因为它们 仅包括已知相互作用的影响。许多临床上重要的DDI需要数年才能发现。鉴于 随着老年人广泛使用多种药物，DDI具有巨大的潜力， 发生在这一人群中，尤其是那些接受华法林或直接口服 抗凝血剂基于已知的代谢途径，这些抗凝剂可能与许多常见的- 处方药涉及抗凝剂的DDI可能导致抗凝过度或抗凝不足， 其中可能会立即危及生命并产生长期后果。 该项目的主要目标是产生临床可操作的和生物学相关的知识， 哪些药物与抗凝剂相互作用导致严重出血和/或血栓栓塞，以及 这种相互作用的时间过程和最易受这些DDI影响的亚组。我们将实现这一目标 目的通过采用转化科学方法进行DDI，其中我们1）进行高通量模拟 基于药理学知识的潜在DDI; 2）对医疗保健进行高通量筛选 数据;然后3）在独立人群中确认（或反驳）并阐明选定的高概率DDI 进行深入的药物流行病学研究。该项目将产生临床可行的 了解哪些药物与抗凝剂相互作用会导致严重出血和/或血栓栓塞， 以及关于药物和这些相互作用中所涉及的途径的可推广的生物学知识。

PROJECT SUMMARY Drug-drug interactions (DDIs) must be regarded not only as a subject for pharmacoepidemiologists and clinical pharmacologists, but as an important issue for public health, particularly in older adults confronted with multiple chronic conditions. Known DDIs are responsible for 13% of adverse drug events and 4.8% of hospital admissions in older adults. Even these high figures may understate the true impact of DDIs because they include only the effects of known interactions. Many clinically important DDIs take years to discover. Given the widespread and growing use of multiple medications by older adults, there is tremendous potential for DDIs to occur in this population, especially among those treated with high risk therapies like warfarin or direct oral anticoagulants. Based on known metabolic pathways, these anticoagulants may interact with many commonly- prescribed medications. DDIs involving anticoagulants can cause over- or under-anticoagulation, the sequelae of which can be immediately life-threatening and have long-term consequences. The broad objective of this project is to produce clinically-actionable and biologically-relevant knowledge about which drugs interact with anticoagulants to cause serious bleeding and/or thromboembolism, as well as the time-course of such interactions and the subgroups most susceptible to these DDIs. We will achieve this objective by taking a translational science approach to DDIs in which we 1) perform high-throughput simulation of potential DDIs based on pharmacologic knowledge; 2) perform high-throughput screening of healthcare data; and then 3) confirm (or refute) and elucidate selected high-probability DDIs in an independent population by conducting in-depth pharmacoepidemiologic studies. This project will produce clinically-actionable knowledge about which drugs interact with anticoagulants to cause serious bleeding and/or thromboembolism, and generalizable biological knowledge about the drugs and pathways involved in these interactions.