奥希替尼上市后安全信号的数据挖掘与分析

Data Mining and Analysis of Safety Signals of Osimertinib after Marketing

目的:挖掘奥希替尼不良事件(ADEs)信号,为其临床用药安全提供参考。方法:采用报告比值比法(ROR)和贝叶斯判别可信区间递进神经网络法(BCPNN)对美国不良事件报告系统(FAERS)中2015年11月-2018年6月报告数≥3的奥希替尼相关ADEs报告进行数据挖掘和信号检测。结果与结论:共挖掘到奥希替尼相关ADEs报告2 044份,其中涉及的女性患者(1 285例)多于男性(615例);报道年龄以45~64岁(228例)、65~74岁(241例)、≥75岁(248例)为主;上报人员以医师(887例)最多。ROR法和BCPNN法分别挖掘到奥希替尼ADEs信号63、57个,后者所得信号均与前者重叠。所得信号包含药品说明书已记载的皮肤毒性(皮炎、皮疹、皮肤干燥、脆甲、指甲功能异常、甲沟炎)、胃肠道反应(食欲减退、腹泻、口腔黏膜炎)、呼吸系统疾病(间质性肺炎、非感染性肺炎)、血液系统疾病(血小板计数降低、白细胞减少、中性粒细胞计数减少)、血管事件(肺栓塞、深静脉血栓)、QTc间期延长等[ROR值为2.04~56.70,信息分数(IC)值为0.97~4.43],以及药品说明书未提及的新的可疑信号如肝损害、脑梗死、低钠血症、房颤、肾损害、脱水、味觉障碍等(ROR值为2.06~161.74,IC值为1.00~4.58)。临床在使用奥希替尼的过程中,除密切关注指(趾)甲毒性、间质性肺炎、QTc间期延长等已知的安全问题外,也应警惕肝损害等潜在ADEs的发生,以保证用药安全。

OBJECTIVE:To mine the signals of osimertinib adverse drug event(ADEs)and to provide reference for clinical drug safety.METHODS:By reporting odd ratio(ROR)and Bayesian confidence propagation neural network(BCPNN)algorithms,data mining and signal detection were carried out on osimertinib-related ADEs reports with case number≥3 reported by American Adverse Event Reporting System(FAERS)from Nov.2015 to Jun.2018.RESULTS&CONCLUSIONS:A total of 2 044 osimertinib-related ADEs were found,among which the female(1 285 cases)was more than the male(615 cases),mainly aged 45-64 years(228 cases),65-74 years(241 cases),≥75 years(248 cases);most of reporters were physicians(887 cases).A total of 63 and 57 osimertinib ADEs signals were mined by ROR and BCPNN methods,and the latter signals overlapped with the former.The obtained signals included skin toxicity(dermatitis acneiform,rash,dry skin,onychoclasis,nail disorder,paronychia),gastrointestinal tract reaction(decreased appetite,diarrhea,stomatitis),respiratory diseases(interstitial pneumonia,pneumonia),hematological diseases(platelet count decreased,white blood cell count decreased,neutrophil count decreased),vascular events(pulmonary embolism,deep vein thrombosis),electrocardiogram QT prolonged(RORs were 2.04-56.70,ICs were 0.97-4.43),all of which had been recorded in drug instructions;obtained signals also included new suspicious signals not indicated in the drug instructions,such as liver damage,cerebral infarction,hyponatremia,atrial fibrillation,renal impairment,dehydration,dysgeusia,and so on(RORs were 2.06-161.74,ICs were 1.00-4.58).In clinical use of osimertinib,besides paying close attention to known safety problems such as nail toxicity of finger(toe)and rash,interstitial pneumonia,electrocardiogram QT prolonged,we should also be alert to the occurrence of potential ADEs such as liver damage to ensure drug safety.