Drugs Associated with Hepatotoxicity and their Reporting Frequency of Liver Adverse Events in VigiBase™ Unified List Based on International Collaborative Work
Drugs Associated with Hepatotoxicity and their Reporting Frequency of Liver Adverse Events in VigiBase™ Unified List Based on International Collaborative Work
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DOI：
10.2165/11535340-000000000-00000
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发表时间：
2010-01-01
期刊：
影响因子：
4.2
通讯作者：
Freston, James W.
中科院分区：
文献类型：
--
作者：
Suzuki, Ayako;Andrade, Raul J.;Freston, James W.
背景资料：在药物性肝损伤（DILI）的临床诊断和获取人类肝毒性信息方面存在挑战：（i）制定一个统一的药物清单，将来自许多公认来源的经过充分审查或裁定的DILI病例中的药物与因肝毒性而受到严重监管的药物相结合;和（ii）用WHO个体病例安全性报告数据库中肝脏事件报告频率的数据补充药物清单（VigiBase（TM））.数据源和提取：（i）在三个主要DILI登记处被确定为DILI原因的药物;（ii）在6个不同数据来源中确定为药物性急性肝衰竭（ALF）原因的药物，包括主要的ALF登记和先前发表的ALF研究;和（iii）在欧洲或美国由于其肝毒性而被鉴定为受到严重政府监管行动的药物。使用VigiBase（TM）确定不良事件的报告频率，计算为经验贝叶斯几何平均值（EBGM），对于两个定制术语“总体肝损伤”和“ALF”具有90%置信区间。EBGM被认为是报告频率的不成比例增加。然后根据地区差异、已发表的病例报告、严重的监管行动以及从VigiBase（TM）计算的“总体肝损伤”和“ALF”的报告频率对所识别的药物进行表征。数据综合：在排除草药、补充剂和替代药物之后，总共识别了385种药物;在3个DILI登记研究中确定了319种药物，107种来自6个ALF登记研究（或研究），47种药物因肝毒性在美国或欧洲暂停或撤回。在西班牙、美国和瑞典之间发现的药物差异很大。在裁定病例的DILI登记研究中确定的319种药物中，93.4%见于已发表的病例报告，1.9%因肝毒性暂停或撤回，25.7%也在ALF登记研究/研究中确定。在VigiBase（TM）中，319种药物中有30.4%与较高的“总体肝损伤”报告频率相关，83.1%与至少一例ALF报告病例相关。这份新开发的肝毒性相关药物清单和对肝毒性的多方面分析将有助于DILI的因果关系评估和临床诊断，并将为肝毒性的进一步表征。
Background: Challenges exist in the clinical diagnosis of drug-induced liver injury (DILI) and in obtaining information on hepatotoxicity in humans.Objective: (i) To develop a unified list that combines drugs incriminated in well vetted or adjudicated DILI cases from many recognized sources and drugs that have been subjected to serious regulatory actions due to hepatotoxicity; and (ii) to supplement the drug list with data on reporting frequencies of liver events in the WHO individual case safety report database (VigiBase (TM)).Data Sources and Extraction: (i) Drugs identified as causes of DILI at three major DILI registries; (ii) drugs identified as causes of drug-induced acute liver failure (ALF) in six different data sources, including major ALF registries and previously published ALF studies; and (iii) drugs identified as being subjected to serious governmental regulatory actions due to their hepatotoxicity in Europe or the US were collected. The reporting frequency of adverse events was determined using VigiBase (TM), computed as Empirical Bayes Geometric Mean (EBGM) with 90% confidence interval for two customized terms, 'overall liver injury' and 'ALF'. EBGM of was considered a disproportional increase in reporting frequency. The identified drugs were then characterized in terms of regional divergence, published case reports, serious regulatory actions, and reporting frequency of 'overall liver injury' and 'ALF' calculated from VigiBase (TM).Data Synthesis: After excluding herbs, supplements and alternative medicines, a total of 385 individual drugs were identified; 319 drugs were identified in the three DILI registries, 107 from the six ALF registries (or studies) and 47 drugs that were subjected to suspension or withdrawal in the US or Europe due to their hepatotoxicity. The identified drugs varied significantly between Spain, the US and Sweden. Of the 319 drugs identified in the DILI registries of adjudicated cases, 93.4% were found in published case reports, 1.9% were suspended or withdrawn due to hepatotoxicity and 25.7% were also identified in the ALF registries/studies. In VigiBase (TM), 30.4% of the 319 drugs were associated with disproportionally higher reporting frequency of 'overall liver injury' and 83.1% were associated with at least one reported case of ALF.Conclusions: This newly developed list of drugs associated with hepatotoxicity and the multifaceted analysis on hepatotoxicity will aid in causality assessment and clinical diagnosis of DILI and will provide a basis for further characterization of hepatotoxicity.