基于openFDA对PARP抑制剂不良事件的信号挖掘与分析

Signal Mining and Analysis of Adverse Events of PARP Inhibitors Based on OpenFDA

目的:挖掘与评价聚腺苷二磷酸核糖聚合酶(PARP)抑制剂的不良事件(ADE)信号,为临床安全合理用药提供参考。方法:通过访问美国食品药品管理局公共数据开放项目(openFDA)数据库药物不良事件端点,检索2004年1月1日~2022年3月31日PARP抑制剂的ADE报告数据,采用报告比值比(ROR)法和英国药品和保健品管理局的综合标准法(以下简称“MHRA法”)进行风险信号挖掘。结果:获得奥拉帕利、尼拉帕利、卢卡帕利和他拉唑帕利的ADE报告分别为8619,13083,7352,672份。4种PARP抑制剂的毒性谱存在一定差异。多数ADE与说明书一致。胃肠道毒性方面,卢卡帕利及尼拉帕利发生恶心、呕吐、消化不良、便秘等信号强度高于奥拉帕利,其中,尼拉帕利发生便秘(ROR=26.77)和肠梗阻(ROR=11.54)的信号强度较高;奥拉帕利和卢卡帕利会引起肠梗阻(ROR=13.84;ROR=6.21)及腹水(ROR=5.71;ROR=5.87),构成比和关联性均较高,但在说明书中未提及;他拉唑帕利在胃肠系统方面较为安全。血液毒性方面,尼拉帕利发生Plt、WBC、RBC降低等信号强度高于其他三者;奥拉帕利发生骨髓增生异常综合征(MDS)(ROR=43.08)和急性髓细胞白血病(AML)(ROR=37.40)的信号强度较高,他拉唑帕利贫血的信号强度最高(ROR=15.96)。此外,尼拉帕利信号强度较高的有失眠(ROR=13.73)、外周神经病变(ROR=18.38)、味觉障碍(ROR=31.23)等。卢卡帕利和奥拉帕利信号强度较高的分别为肾功能损伤(ROR=61.21)和肺炎(ROR=8.79)。结论:临床应用PARP抑制剂时密切监测患者的血常规、肾功能等指标,关注肺炎、肠梗阻、MDS/AML、便秘等ADE信号,进而有效降低临床用药风险。

Objective:To explore and evaluate the safety signals of adverse drug event(ADE)of poly ADP⁃ribose polymerase(PARP)inhibitors,so as to provide reference for clinical safe medication.Methods:The ADE reports of PARP inhibitors from January 1st,2004 to March 31st,2022 were retrieved by visiting the endpoints of the US food and drug ad⁃ministration public data open project(openFDA),and the mined signals were analyzed by reporting odds ratio(ROR)and medicines and health care products regulatory agency(MHRA).Results:A total of 8619 ADE reports of olaparib,13083 ADE reports of niraparib,7352 ADE reports of rucaparib and 672 ADE reports of talazoparib were extracted.The toxicity spectra of four PARP inhibitors showed some differences.Most ADE were in accordance with the instructions.In terms of gastrointestinal toxicity,the risks of nausea,vomiting,dyspepsia,and constipation caused by rucaparib and niraparib were higher than olaparib,among which constipation(ROR=26.77)and intestinal obstruction(ROR=11.54)were the high⁃risk signals for niraparib.Olaparib and rucaparib could cause intestinal obstruction(ROR=13.84;ROR=11.54)and asci⁃tes(ROR=5.71;ROR=9.53),the incidence and correlation was large,but not mentioned in the instruction;talazoparib was safe with respect to the gastrointestinal system.In terms of blood toxicity,niraparib had higher risks of platelet count decreased,white blood cell count decreased and red blood cell count decreased than the other three.Myelodysplastic syn⁃dromes(MDS)(ROR=43.08)and acute myeloid leukemia(AML)(ROR=37.4)were high⁃risk signals for olaparib.Ta⁃lazoparib was at the greatest risk of anemia(ROR=15.96).In addition,insomnia(ROR=13.73),peripheral neuropathy(ROR=18.38),and taste disorder(ROR=31.23)were high signals of niraparib.Renal impairment(ROR=61.21)and pneumonia(ROR=8.79)were high⁃risk signals for rucaparib and olaparib,respectively.Conclusion:The clinical applica⁃tion of PARP inhibitors should be evaluated,especially when the patients have basic diseases such as renal insufficiency,neurological diseases and blood system.Before taking drugs,the patients should be educated,and their blood indexes and kidney functions should be monitored,and pay attention to high⁃risk signals such as pneumonia,intestinal obstruction,MDS/AML,and constipation,effectively,reducing the risk of clinical medication.