Clinical Prediction of Hepatotoxicity & Comparative Hepatic Safety of Medications

描述(由申请人提供)：药物引起的肝毒性，定义为因接触药物而造成的肝脏损伤，是退出市场药物的最常见原因，也是在临床前研究期间终止其他有希望的治疗药物的最常见原因之一。在美国和欧洲，它也是导致肝移植患者急性肝功能衰竭的主要原因。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。鉴于药物引起的肝毒性对临床和公众健康的影响，开发在确定肝毒性时预测肝功能衰竭的可能性的方法，并确定特定药物类别内药物发生肝功能衰竭的相对风险，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，还没有研究得出一种有效的方法来预测一种药物导致肝功能衰竭的可能性，也没有数据比较不同药物类别中与肝功能衰竭相关的风险。为了解决这些问题，这项应用首先寻求开发和验证一个预测性指数，以根据患者进展为肝功能衰竭的风险对肝毒性患者进行分类(目标1)。使用来自北加州凯撒永久医院(KPNC)的数据，我们将首先评估众所周知但未经证实的“Hy定律”的表现，然后寻求改进它，通过修改肝脏转氨酶和总胆红素的临界点，检查它们的上升速度，并评估其他常用的生物标记物是否提高了识别急性肝功能衰竭结果的预测能力。一旦确定了最能预测肝功能衰竭的参数，就会进行内部验证。在研究的第二阶段，将使用国家退伍军人事务部(退伍军人事务部)健康信息系统(AIM 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适性的信息，特别是在AHRQ优先人群中。然后，我们将使用KPNC和退伍军人管理局的数据，比较用于治疗对联邦医疗保险和医疗补助计划至关重要的优先疾病的不同药物所产生的肝功能衰竭的风险(目标3)。我们将首先检查包括已知肝毒性的药物的类别，以确认我们的方法，然后将其他重要类别的药物进行比较。最后，使用目标1中开发的指数，我们将确定目标3中评估的药物类别中的药物的严重肝毒性风险，以提供关于这些药物的相对肝脏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，以显著提高各种优先临床条件下药物治疗的相对安全性和有效性，特别是它们的相对肝脏安全性。 公共卫生相关性：鉴于药物相关性肝毒性的临床和公共卫生意义，开发一种有效的指数来准确识别预测严重肝损伤可能性的信号，将有助于区分严重肝损伤可能性较小的药物治疗方法和那些可能增加肝功能衰竭可能性的药物治疗方法。在药物类别内比较不同药物的使用与肝功能衰竭之间的联系是必要的，以提供这些药物对肝脏的相对安全性的证据，为针对不同条件和环境的适当治疗提供决策依据。

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.