基于美国FAERS数据库对未成年人群肝衰竭ADE信号的挖掘与分析

Mining and analysis for adverse drug event signals of liver failure in underage population based on the FAERS database

目的 基于美国FDA不良事件报告系统(FAERS)数据库,对未成年人群中引起肝衰竭的药物进行数据挖掘,以期为相关药物的临床合理应用提供参考。方法 检索美国FAERS数据库2013年第1季度—2022年第3季度未成年(小于18岁)人群发生肝衰竭的药物不良事件(ADE)报告数据并对其进行挖掘与分析,按不同年龄段分为婴儿(≤1岁)、幼儿(>1~<6岁)、儿童(6~<12岁)和少年(12~<18岁),利用比例失衡法中的报告比值(ROR)法、比例报告比值法和贝叶斯置信区间递进神经网络法筛选ADE信号。结果 共收集到未成年人群的肝衰竭ADE报告1 051份,涉及60种药物。少年的肝衰竭发生率最高(410例,占39.01%),其次是幼儿(297例,占28.26%);有14个药物的说明书未提及肝胆系统损伤和肝衰竭风险,包括左乙拉西坦31例(占2.95%),甲硝唑18例(占1.71%),托吡酯、甲泼尼龙各16例(各占1.52%),地塞米松12例(占1.14%),替沙仑赛11例(占1.05%),硫酸亚铁、二甲双胍和白消安各10例(各占0.95%),丙泊酚9例(占0.86%),onasemnogene abeparvovec 8例(占0.76%),苯海拉明、奥美拉唑各5例(各占0.48%),sebeliesterase α 4例(占0.38%),共计165例,占报告总数的15.70%。其中二甲双胍与已知的肝脏安全性相反;甲硝唑和左乙拉西坦作为新的风险信号,引起的临床结局较为严重。结论 发现了导致未成年人群肝衰竭的14个新的药物警戒信号,在使用这些药物时,应该密切监测患者肝功能,其中二甲双胍既不经过肝脏代谢,也未见相关文献报道,其引发的肝衰竭风险值得进一步关注;甲硝唑和左乙拉西坦引起的临床结局较为严重,需要引起足够重视。

OBJECTIVE To conduct data mining on drugs causing liver failure in underage populations based on the FDA Adverse Event Reporting System(FAERS) database,so as to provide reference for clinical use of related drugs.METHODS The data on reported adverse drug event(ADE) of liver failure in this population(under 18 years old) from the first quarter of 2013 to the third quarter of 2022 were retrieved from the FAERS database for mining and analysis;they were divided into infants(≤1 year old),young children(>1-<6 years old),children(6-<12 years old) and adolescents(12-<18 years old) according to the age.The reporting odds ratio(ROR),proportional reporting ratio and Bayesian confidence propagation neural network of the proportional imbalance method were used to screen ADE signals.RESULTS A total of 1 051 ADE reports of liver failure were collected from the underage population involving 60 drugs.The highest incidence was found in adolescents(410 cases,39.01%),followed by young children(297 cases,28.26%).The instructions of 14 drugs did not mention hepatobiliary system injury and liver failure risk,including 31 cases of levetiracetam(2.95%),18 cases of metronidazole(1.71%),16 cases of each of topiramate and methylprednisolone(1.52% each),12 cases of dexamethasone(1.14%),11 cases of tisagenlecleucel(1.05%),10 cases of each of ferrous sulfate,metformin and busulfan(0.95% each),9 cases of propofol(0.86%),8 cases of onasemnogene abeparvovec(0.76%),5 cases of each of diphenhydramine and omeprazole(0.48% each),4 cases of sebeliesterase α(0.38%),totaling 165 cases,accounting for 15.70% of the total reported cases.Metformin was contrary to the known liver safety,and metronidazole and levetiracetam were new risk signals,which caused more serious clinical outcomes.CONCLUSIONS Fourteen new pharmacovigilance signals which cause liver failure in the underage population are found in this study;the liver function of patients should be closely monitored when using these drugs.Among those drugs,metformin neither undergoes liver metabolism nor has been reported in the relevant literature,and the liver-related ADE caused by metformin deserves further attention.The clinical outcomes caused by metronidazole and levetiracetam are relatively serious and need to be given sufficient attention.