基于美国FDA不良事件报告系统数据库的布格替尼风险信号挖掘

Study on the risk signal mining related to brigatinib based on the US FDA Adverse Event Reporting System

目的挖掘布格替尼不良事件(AE)风险信号,为该药临床安全使用提供参考。方法检索FDA不良事件报告系统数据库,收集2017年4月1日至2022年3月31日以布格替尼为主要怀疑药物的AE报告。采用国际医学用语词典24.0版的首选术语(PT)和系统器官分类(SOC)对AE进行标准化和分类,采用报告比值比(ROR)法和比例报告比值比(PRR)法进行布格替尼AE风险信号挖掘,报告数≥3、ROR≥2且ROR的95%置信区间(CI)下限>1或报告数≥3、PRR≥2且χ^(2)>4的AE定义为阳性信号,对得到的阳性PT信号进行描述性分析。结果纳入分析的AE报告为1564例,涉及672个PT,采用ROR法和PRR法分析,获得52个阳性PT,涉及16个SOC。报告数排在前10位的PT为疲劳、腹泻、恶心、咳嗽、血肌酸磷酸激酶异常、呼吸困难、头痛、皮疹、呕吐和高血压,均为说明书中常见AE;信号强度排在前10位的PT是垂体梗死、放射性坏死、淀粉酶升高、食管静脉曲张、早饱、脂肪酶升高、血肌酸磷酸激酶异常、肺毒性、活化部分凝血活酶时间延长和光敏反应,其中排在第1、2、4、5、8、10位的PT在药品说明书中未见记载。肺炎和间质性肺疾病为布格替尼严重AE,报告数分别为31和8例。52个PT中共有28个在药品说明书中未收录,涉及12个SOC。结论布格替尼的主要不良事件为腹泻、恶心、咳嗽、血肌酸磷酸激酶异常等,其严重AE如肺炎、间质性肺疾病均有报告,与药品说明书记载的常见不良反应一致。此外,布格替尼还可能导致垂体梗死、放射性坏死、肺毒性、光敏反应等,临床应予警惕。

Objective To explore the risk signals of brigatinib-related adverse events(AEs)and provide reference for the safe use in clinical practice.Methods The US FDA Adverse Event Reporting System database was searched and AE reports on brigatinib as the primary suspect drug from April 1,2017 to March 31,2022 were collected.AEs were standardized and classified according to the preferred terms(PT)and system organ class(SOC)of Medical Dictionary for Regulatory Activities 24.0.Reported odds ratio(ROR)and proportional reporting odds ratio(PRR)methods were used to mine the AE risk signals of brigatinib.An AE with reports≥3,ROR≥2,95%confidence interval(CI)lower limit of ROR>1,or reports≥3,PRR≥2,and χ^(2)>4 was defined as a positive signal.Positive PT signals were analyzed using descriptive method.Results Atotalof 1564AEreportswereincludedintheanalysis,involving 672PTs.Afteranalysis using ROR and PRR methods,52 PTs with positive risk signals were obtained,involving 16 SOCs.The top 10 PTs in report amount were fatigue,diarrhea,nausea,cough,abnormal serum creatine phosphokinase,dyspnea,headache,rash,vomiting,and hypertension,all of which were common AEs in the instructions.The top 10 PTs in signal intensity were pituitary infarction,radiation necrosis,elevated amylase,esopha-prolonged activated partial thromboplastin time,and photosensitivity.Among them,the PTs ranked 1st,2nd,4th,5th,8th,and 10th were not recorded in the label.Pneumonia and interstitial lung disease(ILD)were serious AEs,with 31 and 8 reports,respectively.In the 52 PTs,28 were not included in the drug label,involving 12 SOCs.Conclusions The main adverse reactions of brigatinib were diarrhea,nausea,cough,and abnormal serum creatine phosphokinase and serious adverse reactions such as pneumonia and ILD were both reported,which were consistent with the common AE recorded in the drug label.In addition,brigatinib might cause pituitary infarction,radiation necrosis,pulmonary toxicity,photosensitivity,etc.,which should be vigilant in clinical practice.