Clinical Prediction of Hepatotoxicity & Comparative Hepatic Safety of Medications

肝毒性的临床预测

• 批准号: 7984601
• 负责人: VINCENT LO RE
• 金额: $ 49.88万
• 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/7984601
• 关键词: Clinical; Prediction; Hepatotoxicity; Comparative; Hepatic

DESCRIPTION (provided by applicant): 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 referred for 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 application 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 would 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 would be conducted using data from the National Veterans Affairs (VA) Health Information System (Aim 2), which would 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 would 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 would 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. PUBLIC HEALTH RELEVANCE: Given the clinical and public health significance of drug-related hepatotoxicity, the development of a validated index to identify accurately signals that predict the potential for severe hepatic injury would enable differentiation of drug therapies with little likelihood for severe liver injury from those with increased potential for liver failure. Comparing within drug class the association between the use of different medications and liver failure is necessary to provide evidence on the comparative hepatic safety of these medications, informing decision-making about the appropriate treatments for various conditions and settings.

描述（由申请方提供）：药物诱导的肝毒性，定义为药物暴露引起的肝损伤，是撤回上市药物的最常见原因，也是临床前研究期间终止其他有前途的治疗药物的最常见原因之一。它也是美国和欧洲肝移植患者中急性肝衰竭的主要原因。确定药物的相对安全性是比较有效性研究中的一个重要领域。考虑到药物性肝毒性的临床和公共卫生影响，开发预测肝毒性背景下肝衰竭可能性的方法，并确定特定药物类别内药物的肝衰竭相对风险，对于确保药物的相对安全性和有效性至关重要。到目前为止，还没有研究产生一种有效的方法来预测药物导致肝衰竭的可能性，也没有数据比较药物类别中不同药物相关的肝衰竭风险。为了解决这些问题，本申请首先寻求开发和验证一种预测指数，以根据肝毒性患者进展为肝衰竭的风险对其进行分类（目标1）。使用来自Kaiser Permanente北方加州（KPNC）的数据，我们将首先评估众所周知但未经证实的“海氏法则”的性能，然后通过修改肝转氨酶和总胆红素的截止点，检查其上升率，并评估其他常用生物标志物是否提高了识别急性肝衰竭结局的预测能力，来寻求对其进行改进。一旦确定了最佳预测肝衰竭的参数，将进行内部验证。在研究的第二阶段，将利用国家退伍军人事务部卫生信息系统（目标2）的数据对预测指数进行外部验证，该系统将提供关于其普遍性的信息，特别是在AHRQ优先人群中。然后，我们将使用来自KPNC和VA的数据，比较与用于治疗对医疗保险和医疗补助计划重要的优先条件的不同药物相关的肝衰竭风险（目标3）。我们将首先检查包括已知肝毒性药物的类别，以确认我们的方法，然后比较其他重要类别中的药物。最后，使用目标1中开发的指数，我们将确定目标3中评价的药物类别中药物的重度肝毒性风险，以提供这些药物的肝脏安全性比较的进一步证据（目标4）。因此，这一系列研究的总体目标是产生新方法和有价值的数据，这些方法和数据将大大提高药物治疗对各种优先临床疾病的相对安全性和有效性，特别关注其相对肝脏安全性。 公共卫生相关性：考虑到药物相关肝毒性的临床和公共卫生意义，开发一种经验证的指数来准确识别预测重度肝损伤可能性的信号，将能够区分重度肝损伤可能性很小的药物治疗与肝衰竭可能性增加的药物治疗。在药物类别内比较不同药物的使用与肝功能衰竭之间的相关性是必要的，以提供这些药物的比较肝脏安全性的证据，为各种疾病和环境的适当治疗决策提供信息。