伊布替尼单药或联合用药不良反应信号挖掘及影响因素分析

Analysis of adverse reaction signal mining and influencing factors of ibutinib monotherapy versus combination therapy

目的挖掘伊布替尼上市后单药或联合用药不良反应信号,探索伊布替尼相关不良反应的影响因素。方法利用美国食品药品监督管理局不良事件报告系统(FAERS)2014年7月至2022年6月不良事件报告数据,综合运用贝叶斯比例失衡算法中的贝叶斯置信传播神经网络(BCPNN)法和伽玛-泊松分布缩检(GPS)法进行单药不良反应信号挖掘;运用关联规则分析挖掘联合用药不良反应信号;采用贝叶斯网络进行伊布替尼相关心房颤动的影响因素分析。结果BCPNN法共检出单药阳性信号909个,GPS法获得阳性信号739个,前者几乎全部包含了后者,BCPNN法敏感性更高。阳性信号中,大部分为已知的常见不良反应信号,如淋巴细胞增多症(n=244,IC025=3.32)、疲劳(n=4399,IC025=0.32)、腹泻(n=3801,IC025=0.42)、心房颤动(n=3398,IC025=2.06)等;确定了室性心动过速、乙型肝炎病毒再激活、脑血管意外、短暂性脑缺血发作风险;未识别肝损伤风险信号;发现了胸腔积液、骨折、感染性休克、青光眼等多项说明书中未提及的新的不良反应信号。联用异环磷酰胺、替莫唑胺、卡铂、奥妥珠单抗、维奈托克,最有可能导致伊布替尼部分不良反应风险增加,其中影响最大的不良反应为血细胞减少症;性别和适应证是伊布替尼相关性心房颤动是否发生的可能影响因素。结论伊布替尼的整体安全性尚在可接受范围内,但也有部分严重的和新的不良反应信号如室性心动过速、脑血管意外、胸腔积液、骨折、感染性休克等值得临床和研究者进一步关注。

Objective To explore the adverse reaction signals of ibrutinib monotherapy and combination therapy after the marketing,and to explore the influencing factors of ibrutinib-related adverse reactions.Methods Adverse event reporting data from FDA Adverse Event Reporting System(FAERS)from July 2014 to June 2022 were used for data mining,Bayesian Confi?dence Propagation Neural Network(BCPNN)and Gamma Poisson Distribution Reduction(GPS)algorithm were comprehen?sively used to mine single drug adverse reaction signals,and bayesian network methods were used.Using association rule anal?ysis to mine adverse drug reaction signals of combination drugs.Bayesian network was used to analyze the influencing factors of ibutinib related atrial fibrillation.Results A total of 909 positive signals of single drug were detected by BCPNN method,and 739 positive signals were detected by GPS method.The former result almost all contained the latter,and BCPNN method was proved to be more sensitive.Most of the positive signals were common adverse reactions,such as lymphocytosis(n=244,IC025=3.32),fatigue(n=4399,IC025=0.32),diarrhea(n=3801,IC025=0.42),atrial fibrillation(n=3398,IC025=2.06),etc.The risk of ventricular tachycardia,hepatitis B virus reactivation,cerebrovascular accident,and transient ischemic attack were identified.Risk signals of liver injury were not identified.New adverse reaction signals that were not mentioned in the in?structions were found,such as pleural effusion,fracture,septic shock,glaucoma,etc.When given in combination with ifos?famide,temozolomide,carboplatin,otuzumab or venettok,ibrutinib was most likely to increase the risk of some adverse reac?tions,and the most affected adverse reaction was hemocytopenia.(3)Gender and indications were possible factors influencing the occurrence of ibrutinib-associated atrial fibrillation.Conclusion The overall safety of ibrutinib is acceptable,however there are some serious and new adverse reaction signals worthy of further attention of clinical and researchers,such as ventricu?lar tachycardia,cerebrovascular accident,pleural effusion,fracture,septic shock and so on.