Evidence-based Drug-Interaction Discovery: In-Vivo, In-Vitro and Clinical

描述（由申请人提供）：拟议的研究旨在通过关注和利用报告ddi时使用的多种不同类型的证据，为获得关于药物-药物相互作用（ddi）的可靠信息提供有效的、大规模的手段。ddi是药物不良反应的重要原因，导致急诊室就诊和住院。DDI研究旨在通过几种类型的证据，将相互作用背后的分子机制与其实际临床后果联系起来。我们区分了文献中经常提供的三种类型的DDI证据：体外、体内和临床。体外研究探讨相互作用的分子机制；体内研究评估这些相互作用是否会影响人类受试者的药物暴露；临床研究测试药物相互作用是否会改变对药物的实际反应（如药物疗效或药物不良反应）。由于这类研究涉及多个学科，通常这三种类型的证据不能同时获得或报道。这三种类型中任何一种的证据缺失都会造成知识鸿沟，从而阻碍转化研究。例如，如果临床观察到不良相互作用，但分子基础尚未报告，则很难确定安全的替代药物治疗。

DESCRIPTION (provided by applicant): The proposed research aims to provide effective, large-scale means for obtaining reliable information about drug-drug interactions (DDIs), by focusing on and utilizing the multiple distinct types of evidence used in reporting DDIs. DDIs are a significant cause of adverse drug reactions, leading to emergency room visits and hospitalizations. DDI research aims to link between molecular mechanisms that underlie interactions and their actual clinical consequences, through several types of evidence. We distinguish three types of DDI evidence that are often provided in the literature: in vitro, in viv, and clinical. In vitro studies investigate molecular mechanisms of interaction; In vivo studies evaluate whether these interactions impact drug exposure in human subjects; Clinical studies test whether drug interactions change the actual response to drugs (e.g. drug-efficacy or adverse drug reactions). As such studies span several disciplines, typically the three types of evidence are not simultaneously available or reported. Missing evidence along any of the three types, creates a knowledge gap that can hinder translational research. For instance, if adverse interaction effects are clinically observed, but the molecular underpinnings are not yet reported, it is difficult to identify a safe, alternative drug treatment. In this project we propose to develop and use large-scale text-mining methods and tools to mine drug- interaction information from PubMed abstracts and from FDA drug labels. These tools will be designed to explicitly identify gaps across the three levels of DDI evidence, and to help close such gaps. While automated discovery of DDI mentions in text is an active research area, no other text-based work is concerned with identifying explicit evidence for DDI, while separately taking into consideration the distinct types of interaction evidence. As a follow-up step, we also propose to conduct selective molecular pharmacology experiments to close the identified knowledge-gaps at the in vitro evidence level. Specifically: In Aim 1, we shall construct the needed lexica and new text corpora pertaining to in vitro, in vivo, and clinical DDI evidence; In Aim 2, a suite of text mining tools to separately identify the three types of DDI evidence will be developed, utilizing the corpora created in Aim 1; In Aim 3, clinically significant DDIs that have no sufficient in vitro evidence will be selected using the tools developed in Aim 2, and experiments will be conducted to evaluate in vitro metabolic enzyme- based DDI mechanisms. To the best of our knowledge we are the first group that sets out to distinguish among - and make use of - the different types of text-based DDI evidence in a systematic way. Following the text- based discovery with a selective molecular pharmacology experimental evaluation, is another unique interdisciplinary characteristic that adds to the significance of the proposed work. The successful completion of the proposed project will provide methods and tools for large-scale extraction of DDIs from the literature, along with their supporting evidence at the three distinct levels. Moreover, DDIs that will be reliably supported by one type of evidence but not another will be identified as strong candidates for future pharmacology research.