Clinical Prediction of Hepatotoxicity & Comparative Hepatic Safety of Medications

肝毒性的临床预测

• 批准号: 8305407
• 负责人: VINCENT LO RE
• 金额: $ 50万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305407
• 关键词: Clinical; Prediction; Hepatotoxicity; Comparative; Hepatic

Abstract: Drug-induced hepatotoxicity, defined as liver injury caused by exposure to a medication, is the most frequent reason for withdrawal of marketed medications and one of the most common reasons for termination of otherwise promising therapeutic agents during pre-clinical studies. It is also the leading cause of acute liver failure among patients referredfor liver transplantation in both the U.S. and Europe. The determination of the comparative safety of medications is an area of major importance in Comparative Effectiveness Research. Given the clinical and public health impact of drug-induced hepatotoxicity, the development of methods to predict the likelihood of liver failure in the setting of hepatotoxicity and determination of the comparative risk of liver failure for medications within particular drug classes are crucial to ensuring the comparative safety and effectiveness of medications. To date, no studies have yet yielded a validated method to predict the potential for a medication to lead to liver failure, and no data have compared the risk of liver failure associated with different medications within drug classes. To address these issues, this proposal first seeks to develop and validate a predictive index to classify patients with hepatotoxicity by their risk of progression to liver failure (Aim 1). Using data from Kaiser Permanente Northern California (KPNC), we will start by evaluating the performance of the well known but unproven "Hy's Law", and then seek to improve upon it, by modifying cut-off points for liver aminotransferases and total bilirubin, examining their rate of rise, and evaluating whether additional commonly available biomarkers improve predictive ability to identify outcomes of acute liver failure. Once the parameters that best predict liver failure are determined, internal validation will be performed. In the second phase of the study, external validation of the predictive index will be conducted using data from the National Veterans Affairs (VA) Health Information System (Aim 2), which will provide information on its generalizability, particularly in AHRQ priority populations. We will then compare the risk of liver failure associated with different medications used for the treatment of priority conditions of importance to the Medicare and Medicaid programs using data from both KPNC and the VA (Aim 3). We will first examine classes that include a medication with known hepatotoxicity, to confirm our approach, and then compare medications within other important classes. Finally, using the index developed in Aim 1, we will determine the risk of severe hepatotoxicity for medications in the drug classes evaluated in Aim 3, to provide further evidence on the comparative hepatic safety of these medications (Aim 4). Thus, the overall goal of this series of studies is to produce new methods and valuable data that will enhance substantially the comparative safety and effectiveness of drug therapies for a variety of priority clinical conditions, with a particular focus on their comparative hepatic safety.

摘要： 药物引起的肝毒性是最常见的，定义为因接触药物而导致的肝损伤。 撤回上市药物的原因和终止上市药物的最常见原因之一 在临床前研究中，其他很有希望的治疗药物。它也是引起急性肝病的主要原因。 在美国和欧洲，转诊进行肝移植的患者中均有失败。这一决定决定了 药物的比较安全性是比较有效性研究中的一个重要领域。 鉴于药物引起的肝毒性对临床和公共健康的影响，开发方法来 在肝毒性设定和确定肝功能衰竭的相对风险中预测肝衰竭的可能性 在特定药物类别内的药物引起的肝功能衰竭是确保相对安全性和 药物的有效性。到目前为止，还没有研究出一种经过验证的方法来预测潜在的 对于一种导致肝功能衰竭的药物，没有数据比较与 药物类别内的不同药物。 为了解决这些问题，这项提议首先寻求开发和验证一个预测性指数来分类 因进展为肝功能衰竭的风险而出现肝毒性的患者(目标1)。使用来自Kaiser的数据 北加州(KPNC)，我们将从评估众所周知的但 未经证实的“Hy定律”，然后试图通过修改肝脏转氨酶的临界点来改进它 和总胆红素，检查它们的上升速度，并评估是否有额外的普遍可用 生物标记物提高了识别急性肝功能衰竭结果的预测能力。一旦最好的参数 预测肝功能衰竭已确定，将进行内部验证。在研究的第二阶段， 预测性指数的外部验证将使用国家退伍军人事务部(VA)的数据进行 保健信息系统(AIM 2)，将提供关于其普适性的信息，特别是在AHRQ 优先人群。然后，我们将比较使用不同药物治疗肝功能衰竭的风险。 使用来自医疗保险和医疗补助计划的数据处理对医疗保险和医疗补助计划重要的优先条件 KPNC和退伍军人事务部(目标3)。我们将首先审查包括已知肝毒性药物在内的课程， 以确认我们的方法，然后比较其他重要类别的药物。最后，使用索引 在目标1中开发，我们将确定药物类别中的药物的严重肝毒性风险 在目标3中进行评估，以提供这些药物对肝脏的相对安全性的进一步证据(目标4)。 因此，这一系列研究的总体目标是产生新的方法和有价值的数据，以增强 基本上，各种优先临床药物疗法的相对安全性和有效性 条件，并特别关注其相对肝脏的安全性。