Drug-Drug Interactions Involving Antidiabetic Agents

描述(由申请人提供)：已知的药物-药物相互作用(DDIS)导致13%的药物不良事件和4.8%的老年人住院。即使是这些高数字也可能低估了DDIS的真实影响，因为它们只包括已知相互作用的影响。许多临床上重要的DDIS需要数年时间才能发现。考虑到糖尿病患者广泛且越来越多地使用多种药物，DDIS在这一人群中发生的可能性很大。在十种最常用的二线抗糖尿病药物中，有五种是胰岛素促分泌剂，根据已知的代谢途径，它可能会与许多常用的处方药相互作用。涉及胰岛素促分泌剂的DDIS可导致严重的低血糖，这可能立即危及生命，并造成长期后果。这个项目的广泛目标是产生临床可操作的知识，关于哪些药物与胰岛素分泌剂相互作用会导致严重的低血糖，以及这种相互作用的时间进程和最容易受到这些DDIS影响的亚群。我们将通过对DDIS采取翻译科学的方法来实现这一目标，其中我们1)基于药理学知识对潜在的DDIS进行高通量模拟；2)对医疗数据进行高通量筛选；然后3)通过进行深入的药物流行病学研究，在独立人群中确认(或驳斥)和阐明选定的高概率DDIS。该项目将产生关于哪些药物与促分泌剂相互作用导致严重低血糖的临床可操作知识，以及关于参与这些相互作用的药物和途径的可推广的生物学知识。

DESCRIPTION (provided by applicant): Known drug-drug interactions (DDIs) are responsible for 13 percent of adverse drug events and 4.8 percent 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 persons with diabetes, there is tremendous potential for DDIs to occur in this population. Of the ten most commonly used second-line antidiabetic agents, five are insulin secretagogues, which, based on known metabolic pathways, may interact with many commonly- prescribed medications. DDIs involving insulin secretagogues can cause serious hypoglycemia, which can be immediately life-threatening and have cause long-term consequences. The broad objective of this project is to produce clinically-actionable knowledge about which drugs interact with insulin secretagogues to cause serious hypoglycemia, 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 secretagogues to cause severe hypoglycemia, and generalizable biological knowledge about the drugs and pathways involved in these interactions.