4个进口PD-1/PD-L1抑制剂不良反应信号的挖掘与评价

Excavation and evaluation of adverse reaction signals of 4 kinds of imported PD-1/PD-L1 inhibitors

目的 挖掘和评价4个进口程序性死亡蛋白1(PD-1)及其配体(PD-L1)抑制剂上市后的不良反应信号,以期指导临床合理用药。方法 利用OpenVigil 2.1软件从美国FDA不良事件报告系统获取2013年第1季度至2020年第4季度纳武利尤单抗、帕博利珠单抗、阿替利珠单抗和度伐利尤单抗的不良事件报告,并采用报告比值比法和比例报告比法进行信号挖掘,评价新的或潜在的不良反应信号。结果 共收集到46 840份以PD-1/PD-L1抑制剂为首要怀疑药物的不良事件报告,其中纳武利尤单抗28 896份、帕博利珠单抗13 298份、阿替利珠单抗3 398份、度伐利尤单抗1 248份。从不良事件报告的基本情况来看,男性多于女性,年龄集中于51~85岁,报告年份集中于近4~5年,报告国家以美国和日本为主,报告结局显示4个药物严重不良事件的上报比例都超过了50%,且以“死亡”“住院或住院时间延长”为主。共挖掘得到不良反应信号1 597个,累及系统器官26个,主要集中在“良性、恶性及性质不明的肿瘤(包括囊状和息肉状)”“感染及侵染类疾病”“各类检查”等方面。对频数排名前50位的不良反应信号进行分析发现,“内分泌系统疾病”含有的不良反应信号最多,“恶性肿瘤进展”的信号频数最大,“放射性肺炎”的信号强度最大;“放射性肺炎”“胆管炎”“暴发性1型糖尿病”“血肌酸磷酸激酶升高”“弥散性血管内凝血”“心力衰竭”“大脑梗死”等13个不良反应信号在药品说明书中未曾报告。结论 PD-1/PD-L1抑制剂介导产生的不良反应信号众多,在“良性、恶性及性质不明的肿瘤(包括囊状和息肉状)”“感染及侵染类疾病”“各类检查”等方面的安全风险较高;新发现的“放射性肺炎”“胆管炎”“血肌酸磷酸激酶升高”“心力衰竭”“大脑梗死”等13个不良反应信号对于指导临床合理用药具有重要意义。

OBJECTIVE To excavate and evaluate the adverse reaction signals of 4 kinds of imported programmed cell death 1(PD-1)and its ligand(PD-L1)inhibitors,and to guide rational drug use in clinic. METHODS OpenVigil 2.1 software was used to obtain the adverse event reports of four drugs as nivolumab,pembrolizumab,atezolizumab and durvalumab from the first quarter of 2013 to the fourth quarter of 2020 in the US FDA adverse event reporting system. The reporting odds ratio and proportional reporting ratio were used for signal mining to evaluate new or potential adverse reaction signals. RESULTS A total of 46 840reports of adverse events with PD-1/PD-L1 inhibitors as the primary suspected drug were collected,including 28 896 reports of nivolumab,13 298 reports of pembrolizumab,3 398 reports of atezolizumab,and 1 248 reports of durvalumab. From the general characteristics of these reports,the gender distribution was more men than women,and the age distribution was mainly in the range of 51-85 years old. The reporting year was mainly in the nearly 4-5 years,and the main reporting countries were the US and Japan,with“death”and“hospitalization or prolonged hospitalization”as the main serious adverse events which were over 50% of the whole of 4 kinds of adverse events. A total of 1 597 adverse reaction signals were obtained,involving 26 systems,focusing on“benign,malignant and unspecified neoplasms(cystic and polypoid tumor)”,“infections and infestations”and“investigations”,etc. The analysis of the top 50 adverse reaction signals showed that the largest number of report was endocrine system disease,the most frequency signal was“malignant neoplasm progression”and the strongest adverse reaction signal was“radiation pneumonitis”.And it was also found that 13 adverse reaction signals,such as“radiation pneumonitis”“cholangitis”“fulminant type 1 diabetes mellitus” “blood creatine phosphokinase increased”“disseminated intravascular coagulation”“cardiac failure”and“cerebral infarction”, etc., were not reported in the drug instructions. CONCLUSIONS PD-1/PD-L1 inhibitors mediate a large number of adverse reaction signals,resulting in high safety risks in“benign,malignant and unspecified neoplasms(cystic and polypoid tumor)”,“infections and infestations”and“investigations”,etc. The newly discovered 13 adverse reaction signals,such as“radiation pneumonitis”“cholangitis”“blood creatine phosphokinase increased”“cardiac failure”and“cerebral infarction”are of great significance for guiding rational drug use in clinic.