乌帕替尼上市后不良反应评估：一项基于美国FDA不良事件报告系统数据库的真实世界研究

摘要/Abstract

摘要： 目的：通过美国FDA不良事件报告系统(FDA Adverse Event Reporting System， FAERS)系统数据库，挖掘与分析乌帕替尼上市后药品不良事件（Adverse event， AE）信号，为其临床用药安全提供参考。方法：从FAERS数据库提取2019年第3季度至2023年第1季度的不良事件报告数据，采用报告比值比法（Reporting odds ratio， ROR）和比例报告比值法（Proportional reporting ratio， PRR）对乌帕替尼相关的不良事件报告进行信号挖掘与分析。结果：共提取了28 743份以乌帕替尼为首要怀疑的不良事件报告，检测出315个阳性信号，涉及20个系统器官分类( System organ class， SOC)。阳性信号涉及SOC主要为“感染及侵染类疾病”、“各类损伤、中毒及操作并发症”、及“各种肌肉骨骼及结缔组织疾病”。报告频次前5位的信号的首选术语（Preferred terms， PT）为疼痛、COVID-19、肢体疼痛、肌肉骨骼强直、尿路感染。信号强度较高但说明书未记载的信号有握力减弱、腕管综合征、肌腱断裂、肌肉骨骼强直、白内障等。严重不良事件结果对应的PT主要为COVID-19、感染性肺炎心血管疾病、脑血管意外等。结论：临床使用乌帕替尼时，除需关注疼痛、感染等常见不良事件及说明书未提及的新不良事件外，还应重视严重感染、心脑血管意外、肺栓塞等严重不良事件结局检出的信号。

关键词: font-size:medium, ">乌帕替尼；美国FDA不良事件报告系统；信号分析；报告比值比法；比例报告比值法；不良事件

Abstract: Objective： To explore the adverse event(AE) signals of upadacitinib in real-world by the US Food and Drug Administration Adverse Event Reporting System(FAERS) and improve the clinical safety of upadacitinib. Methods： The data from 2019Q3 to 2023Q1 adverse event reports in the FAERS were obtained. The reporting odds ratio(ROR) and proportional reporting ratio(PRR) were used to detect the risk signals of upadacitinib. Results： Totally 28743 AE reports which took the upadacitinib as the primary suspect(PS) drug were obtained from FAERs database， and 315 positive signals involving 20 system organ class(SOC) were detected. The positive signals most releted SOC were “infections and infestations”， “injury， poisoning and procedural complications”， “musculoskeletal and connective tissue disorders”. The top 5 frequently reported PTs were pain， COVID-19，pneumonia， pain in extremity， urinary tract infection. Some new signals with high ROR were found included grip strength decreased， carpal tunnel syndrome，tendon rupture， musculoskeletal stiffness， cataract.The serious outcomes main related PTs were COVID-19， pneumonia， cardiovascular disease， cerebrovascular accident. Conclusion： In clinical， We must pay attentation to the common adverse event for upadacitinib and the new PTs which were not listed in the label. Meanwhile， clinicians and pharmacists to enhance their vigilance for the outcome of serious adverse events of upadacitinib and the corresponding detection signals， such as serious pneumonia， cardiovascular disease， cerebrovascular accident.

Key words: font-size:medium, ">Upadacitinib； FDA Adverse Event Reporting System（FAERS)； Data mining； Reporting odds ratio； Proportional reporting ratio； Adverse event

中图分类号:

史华慧, 许志强, 季春梅. 乌帕替尼上市后不良反应评估：一项基于美国FDA不良事件报告系统数据库的真实世界研究[J]. 中国药物评价, 2024, 41(5): 419-423.

SHI Hua-hui, XU Zhi-qiang, JI Chun-mei. Evaluation of Adverse events of Upadacitinib：a Real-world Study Based on the US Food and Drug Administration Adverse Event Reporting System[J]. CHINESE JOURNAL OF DRUG EVALUATION, 2024, 41(5): 419-423.

参考文献

[1] Duggan S， Keams J. Upadacitinib： First Approval[J]. Drugs， 2019， 79(16)： 1819-1828.
     [2] Sanmarti R， Corominas H. Upadacitinib for Patients with Rheumatoid Arthritis： A Comprehensive Review[J]. J Clin Med， 2023， 12(5)： 1734.
     [3] Banerjee S， Biehl A， Gadina M， et al. JAK-STAT Signaling as a Target for Inflammatory and Autoimmune Diseases： Current and Future Prospects[J]. Drugs， 2017， 77(5)： 521-546.
     [4] 邹雪，张丽卿. Janus激酶抑制剂及其在类风湿关节炎治疗中的作用研究进展[J]. 山东医药， 2022， 62(31)： 107-110.
     [5] 杨宇. 乌帕替尼(Upadacitinib，Rinvoq)[J]. 中国药物化学杂志， 2020， 30(7)： 450.
     [6] 杨成兵. 治疗类风湿关节炎新药upadacitinib[J]. 中国新药杂志， 2020， 29(22)： 2561-2564.
     [7] 王文社，苏茵，贾园. 乌帕替尼在风湿免疫领域临床研究进展[J]. 中国新药杂志， 2022， 31(23)： 2289-2295.
     [8] 何石焕，刘京平. 乌帕替尼治疗特应性皮炎的研究进展[J]. 现代医药卫生， 2022， 38(20)： 3508-3516.
     [9] Smolen JS， Pangan AL， Emery P， et al. Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response to methotrexate（SELECT-MONOTHERAPY)： a randomised， placebo-controlled， double-blind phase 3 study[J]. Lancet， 2019， 393(10188)： 2303-2311.
     [10] Van Vollenhoven R， Takeuchi T， Pangan AL， et al. Efficacy and Safety of Upadacitinib Monotherapy in Methotrexate-Naive Patients With Moderately-to-Severely Active Rheumatoid Arthritis（SELECT-EARLY)： A Multicenter， Multi-Country， Randomized， Double-Blind， Active Comparator-Controlled Trial[J]. Arthritis Rheumatol， 2020， 72(10)： 1607-1620.
     [11] Sakaeda T， Tamon A， Kadoyama K， et al. Data mining of the public version of the FDA Adverse Event Reporting System[J]. Int J Med Sci， 2013， 10(7)： 796-803.
     [12] Liu Y， Dong C， He X， et al. Post-Marketing Safety of Vemurafenib： A Real-World Pharmacovigilance Study of the FDA Adverse Event Reporting System[J]. J Pharm Pharm Sci， 2022， 25： 377-390.
     [13] Cohen SB， Van Vollenhoven RF， Winthrop KL， et al. Safety profile of upadacitinib in rheumatoid arthritis： integrated analysis from the SELECT phase Ⅲ clinical programme[J]. Ann Rheum Dis， 2021， 80(3)： 304-311.
     [14] Clarke B， Yates M， Adas M， et al. The safety of JAK-1 inhibitors[J]. Rheumatology（Oxford)， 2021， 60(Suppl 2)： ii24-ii30.
     [15] Burmester GR， Cohen SB， Winthrop KL， et al. Safety profile of upadacitinib over 15 000 patient-years across rheumatoid arthritis， psoriatic arthritis， ankylosing spondylitis and atopic dermatitis[J]. RMD Open， 2023， 9(1)： e002735.
     [16] 吴景华，郭佳培，王志刚，等. IL-6-JAK2/STAT3信号途径在骨质疏松症的作用机制研究[J]. 现代预防医学， 2016， 43(14)： 2621-2623.
     [17] 徐水明，许俊来，曾国兴，等. 托法替布治疗类风湿关节炎患者的骨代谢指标改善情况[J]. 广东医学， 2022， 43(5)： 631-634.
     [18] Adami G， Saag KG. Osteoporosis Pathophysiology， Epidemiology， and Screening in Rheumatoid Arthritis[J]. Curr Rheumatol Rep， 2019， 21(7)： 34.
     [19] 伍俊妍，邱凯锋. JAK抑制剂临床用药指引[J]. 今日药学， 2023，33(6)：401-413.
     [20] 加拿大提示JAK抑制剂(托法替布、巴瑞替尼、乌帕替尼)严重心脏相关问题、血栓、癌症和死亡的潜在风险[J]. 中国医药导刊， 2022， 24(11)： 1078.
     [21] Benucci M， Damiani A， Infantino M， et al. Cardiovascular safety， cancer and Jak-inhibitors： Differences to be highlighted[J]. Pharmacol Res， 2022， 183： 106359.