基于美国FDA不良事件报告系统数据库的地舒单抗风险信号挖掘

Study on the risk signal mining related to denosumab based on the US Food and Drug Administra⁃tion Adverse Event Reporting System

目的了解地舒单抗的主要不良事件(AE)及其发生风险,为该药临床安全应用提供参考。方法收集美国FDA不良事件报告系统数据库2010年第2季度至2021年第1季度收录的地舒单抗AE报告,采用比例报告比值比(PRR)法进行AE风险信号挖掘。AE报告数≥3、PRR≥2且χ2≥4的AE被定义为阳性风险信号。采用国际医学用语词典(MedDRA)v24.0的首选系统器官分类(SOC)和首选术语(PT)对AE进行分类统计,选取AE报告数和信号强度排名前50位的PT进行分析。结果共收集到以地舒单抗为首要怀疑药物的AE报告132764例,涉及PT 5571个,筛选出阳性风险信号641个。经第2次筛选,获得AE报告数排名前50位和PRR值排名前50位的PT,筛重后纳入分析的PT为93个,涉及AE报告114617例。AE报告数居前5位的PT为未依说明书用药(28.7%,32863/114617)、死亡(14.2%,16230/114617)、颌骨骨坏死(6.0%,6861/114617)、关节痛(4.7%,5420/114617)和四肢疼痛(4.1%,4727/114617);信号强度居前5位的PT为骨巨细胞瘤(PRR=402.7)、恶性骨巨细胞瘤(PRR=325.2)、C-端肽增加(PRR=169.4)、颌骨外生骨疣(PRR=163.2)、钙离子异常(PRR=158.1)。涉及AE报告数居前5位的SOC依次为各类损伤、中毒及操作并发症(35.9%,41757/114617),各种肌肉、骨骼及结缔组织疾病(32.7%,37455/114617),全身性疾病及给药部位各种反应(18.2%,20814/114617),各种手术及医疗操作(4.1%,4744/114617),以及各类检查(2.9%,3290/114617)。44个PT在药品说明书中未收录,其中23个与口腔有关。结论地舒单抗报告数较多的AE为未依说明书用药和颌骨骨坏死,颌骨骨坏死、骨巨细胞瘤复发或恶化风险信号较强;挖掘出说明书中未收录的AE风险信号多数为口腔问题。

Objective To understand the main adverse event(AE)related to denosumab and the risks and provide reference for the safe use of the drug in clinic.Methods The AE reports on deno⁃sumab included in the US FDA Adverse Event Reporting System from the second quarter of 2010 to the first quarter of 2021 were collected,and the AE risk signals was explored using proportional reporting odds ratio(PRR)method.AEs with≥3 reports,PRR value≥2,andχ²≥4 were defined as positive risk signals.AEs were counted and classified using the preferred system organ class(SOC)and preferred term(PT)of Medical Dictionary for Regulatory Activities 24.0.The PTs of top 50 adverse event reports and signal intensity were selected and analyzed.Results A total of 132764 AE reports with denosumab as the primary suspected drug were collected,involving 5571 PTs,and 641 positive risk signals were selected.After the second screening,the top 50 PTs in the number of AE reports and the top 50 PTs with great PRR values were obtained,and 93 PTs were included in the analysis after sifting out the repeated,involving 114617 AE reports.The top 5 PTs in the number of AE reports were off⁃label use(28.7%,32863/114617),death(14.2%,16230/114617),osteonecrosis of the jaw(6.0%,6861/114617),arthralgia(4.7%,5420/114617),and limb pain(4.1%,4727/114617).The top 5 PTs with the high signal intensity were giant⁃cell tumour of bone(PRR=402.7),malignant giant⁃cell tumour of bone(PRR=325.2),C⁃telopeptide increase(PRR=169.4),exostosis of jaw(PRR=163.2),and ionised calcium abnormal(PRR=158.1).The top 5 SOC involving AE reports were injury,poisoning and procedural complications(35.9%,41757/114617),musculoskeletal and connective tissue disorders(32.7%,37455/114617),general disorders and administration site conditions(18.2%,20814/114617),surgical and medical procedures(4.1%,4744/114617),and investigations(2.9%,3290/114617).Forty⁃four PTs were not included in the drug instructions,of which 23 were related to the oral cavity.Conclusions Denosumab AE with the most reports were off-label use and osteonecrosis of the jaw.The risk signals of osteonecrosis of the jaw and recurrence or deterioration of giant⁃cell tumor of bone was strong.Most of the AE risk signals that were not included in the instructions are oral problems.