Drug-induced liver injury in humans: the case of ximelagatran.
Drug-induced liver injury in humans: the case of ximelagatran.
复制标题
DOI：
10.1007/978-3-642-00663-0_13
复制
发表时间：
2010-01-01
影响因子：
--
通讯作者：
Andersson, T B
中科院分区：
文献类型：
--
作者：
Keisu, M;Andersson, T B
Ximelagatran是临床开发中的第一个口服直接凝血酶抑制剂，也进入了市场。Ximelagatran在一项广泛的临床计划中进行了测试。短期(35天)使用西美拉格兰(>；3倍正常(ULN)血浆ALT上限的发生率为7.9%)。西美拉格伦组和对照组总胆红素水平升高的频率相似。然而，丙氨酸氨基转移酶3x ULN和总胆红素2xULN的组合在服用西美拉格伦的患者中为0.5%，在对照组患者中为0.1%。发烧和皮疹等可能表明过敏(免疫学反应类型)的症状较低，在西美拉格伦和对照组之间没有差异。一项为期35天的研究的安全性数据表明，患者在完成药物暴露后可能会出现严重的肝损伤，定期的肝功能监测可能不会降低可能出现的严重肝损伤的风险，从而触发了西美拉格伦退出市场和终止西美拉格兰开发计划。至于许多导致肝损伤的药物，标准的临床前毒理学研究没有提供任何迹象表明西美拉格兰影响肝功能。此外，使用基于人类的体外模型进行的广泛研究还不能确定解释长期临床试验中观察到的肝损伤模式的机制。药物基因组学研究表明，ALT升高与主要组织相容性复合体(MHC)等位基因DRB1‘07和DQA1*02有关，提示可能是免疫原性致病机制。这一例子为特殊药物所致肝毒性的机制提供了重要线索。
Ximelagatran was the first orally available direct thrombin inhibitor under clinical development that also reached the market. Ximelagatran was tested in an extensive clinical programme. Short-term use (35 days) use of ximelagatran (incidence of >3x upper limit of normal (ULN) plasma ALT was 7.9%). The frequency of elevated total bilirubin levels was similar in the ximelagatran and the comparator groups. However, the combination of ALT > 3x ULN and total bilirubin > 2xULN was 0.5% among patients treated with ximelagatran and 0.1% among patients in the comparator group. Symptoms such as fever and rash potentially indicating hypersensitivity (immunologic type of reaction) were low and did not differ between ximelagatran and the comparators. The withdrawal of ximelagatran from the market and termination of the ximelagatran development program was triggered by safety data from a 35-day study, indicating that severe hepatic injury in a patient could develop after exposure to the drug has been completed and that regular liver function monitoring may not mitigate the possible risk of severe hepatic injury. As for many drugs causing liver injury, the standard preclinical toxicological studies provided no indication that ximelagatran affected hepatic functions. In addition, extensive investigations using human-based in vitro models have not been able to define mechanisms explaining the pattern of hepatic injury observed in long-term clinical trials. A pharmacogenomic study provided evidence that the ALT increases were associated with major histocompatibility complex (MHC) alleles DRB1'07 and DQA1*02 suggesting a possible immunogenic pathogenesis. This example provides important clues to the mechanism of idiosyncratic drug-induced liver toxicity.