CDK4/6抑制剂不良反应评估：基于FAERS数据库的真实世界研究

佘友俊; 郭子寒; 张忠伟; 杜琼

doi:10.19401/j.cnki.1007-3639.2023.10.003

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CDK4/6抑制剂不良反应评估：基于FAERS数据库的真实世界研究

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- CDK4/6抑制剂不良反应评估：基于FAERS数据库的真实世界研究
- Evaluation of adverse events of CDK4/6 inhibitors: a real-world study based on the FAERS database
- 中国癌症杂志 2023年33卷第10期页码：908-919
- 作者机构：
  
  1. 复旦大学附属肿瘤医院药剂科，复旦大学上海医学院肿瘤学系，上海 200032
  2. 复旦大学附属肿瘤医院重症医学科，复旦大学上海医学院肿瘤学系，上海 200032
- 作者简介：
  
  [ "佘友俊（ORCID: 0000-0001-9616-7005），药学硕士，初级药师。" ]
  杜琼（ORCID: 0000-0003-4830-9704），药学硕士，主管药师。
- 基金信息：
  
  上海市抗癌协会“翱翔计划”项目(SHAX-QT-202101)
- DOI：10.19401/j.cnki.1007-3639.2023.10.003
  中图分类号： R730.51
- 收稿：2023-07-19，
  
  修回：2023-10-18，
  
  纸质出版：2023-10-30
- 稿件说明：
移动端阅览
佘友俊, 郭子寒, 张忠伟, 等. CDK4/6抑制剂不良反应评估：基于FAERS数据库的真实世界研究[J]. 中国癌症杂志, 2023,33(10):908-919.

Youjun SHE, Zihan GUO, Zhongwei ZHANG, et al. Evaluation of adverse events of CDK4/6 inhibitors: a real-world study based on the FAERS database[J]. China Oncology, 2023, 33(10): 908-919.
佘友俊, 郭子寒, 张忠伟, 等. CDK4/6抑制剂不良反应评估：基于FAERS数据库的真实世界研究[J]. 中国癌症杂志, 2023,33(10):908-919. DOI： 10.19401/j.cnki.1007-3639.2023.10.003.

Youjun SHE, Zihan GUO, Zhongwei ZHANG, et al. Evaluation of adverse events of CDK4/6 inhibitors: a real-world study based on the FAERS database[J]. China Oncology, 2023, 33(10): 908-919. DOI： 10.19401/j.cnki.1007-3639.2023.10.003.

摘要

背景与目的：

细胞周期蛋白依赖性激酶4和6（cyclin-dependent kinase 4/6，CDK4/6）抑制剂的开发和批准是激素受

体阳性转移性乳腺癌治疗的一个重要里程碑。这类药物疗效相似，但不良事件（adverse events，AE）各有不同，直接影响临床用药选择。目前关于CDK4/6抑制剂的安全性在真实世界中的系统研究尚不全面。而本研究则通过对美国食品药品管理局（Food And Drug Administration，FDA）不良事件报告系统（FDA Adverse Event Reporting System，FAERS）进行信号挖掘，比较CDK4/6抑制剂AE的差异，发现未知AE信息，旨在为临床治疗方案的选择和AE监测提供参考依据。

方法：

提取FAERS数据库中2014年第一季度至2023年第一季度的所有数据，去除重复报告后，对将“palbociclib（哌柏西利）”、“abemaciclib（阿贝西利）”和“ribociclib（瑞波西利）”列为“首要怀疑”的报告，通过比例失衡测量法进行数据分析。本研究采用报告比值比（reporting odds ratio，ROR）法和MHRA法识别信号，阳性信号需要同时满足：报告数≥3、ROR的95%置信区间的下限

1、比例报告比值比（proportional reporting ratios，PRR）

2、

4的标准。

结果：

研究选出85 562条与CDK4/6抑制剂相关的AE报告。哌柏西利在血液学和淋巴系统AE中信号最强（白细胞减少症ROR = 20.01）。在胃肠道系统和肝肾系统中，哌柏西利的AE信号较其他药物低（腹泻ROR = 1.95，γ-谷氨酰转移酶升高ROR = 0.36，血肌酐升高ROR = 1.01）。阿贝西利在胃肠道系统信号最强（腹泻ROR = 13.54）；在肝肾系统也表现出较强的AE信号（γ-谷氨酰转移酶升高ROR = 2.58，血肌酐升高ROR = 7.74）；在血液和淋巴系统AE信号较其他药物低（白细胞减少ROR = 5.34）。瑞波西利在血液和淋巴系统中的AE信号强度低于哌柏西利（白细胞减少症ROR = 7.55）；但在肝肾系统AE中，瑞波西利的γ-谷氨酰转移酶升高信号强度最高（ROR = 4.05）。另外，在罕见严重的肝脏AE中，阿贝西利肝衰竭（ROR = 3.50）和药物诱导的肝损伤（ROR = 4.68）信号最强。研究还发现多形性红斑（ROR = 3.06）是阿贝西利新的AE信号。

结论：

CDK4/6抑制剂安全性的特点各不相同。对FAERS数据库的分析揭示哌柏西利和瑞波西利有血液和淋巴系统毒性、阿贝西利存在胃肠道毒性和肝毒性。研究同时发现阿贝西利严重AE为多形性红斑。结果提示，治疗期间医疗人员需要依据患者生理状态和药物AE的特点进行个体化用药选择和AE监测。

Abstract

Background and purpose:

The development and approval of inhibitors of cyclin-dependent kinase 4/6 (CDK4/6) is an essential milestone in treating hormone receptor-positive metastatic breast cancer. The efficacy of these drugs is similar

but the adverse events (AE) are different

directly affecting the physician's choice of drug. There is no systematic study on the safety of CDK4/6 inhibitors in the real world. In this study

we compared the differences in AE of CDK4/6 inhibitors through signal mining in the FDA Adverse Event Reporting System (FAERS) and identified unknown AE signals to provide a reference for the clinical choice of treatment and monitoring AE.

Methods:

All data in the FAERS database were extracted from

the first quarter of 2004 to the first quarter of 2023. After removing duplicates

data were analyzed by the disproportionality method for reports ranking palbociclib

abemaciclib

or ribociclib as the primary suspect. Signals were identified using the reporting odds ratio (ROR) and MHRA methods. Positive signals were required to meet the following criteria: the number of reports ≥3

the lower limit of the 95% confidence interval of the ROR

proportional reporting ratios (PRR)

and the

Results:

A total of 85 562 reports of AE associated with CDK4/6 inhibitors were identified. The highest signal intensity of palbociclib was observed in hematologic and lymphatic AE (leukopenia ROR = 20.01). Palbociclib had lower AE signals in the gastrointestinal

hepatic

and renal systems than the other drugs (diarrhea ROR = 1.95

gamma-glutamyltransferase increased ROR = 0.36

blood creatinine increased ROR = 1.01). Abemaciclib had the strongest signal in the gastrointestinal system (diarrhea ROR = 13.54); it also showed a strong AE signal in the hepatic and renal systems (gamma-glutamyltransferase increased ROR = 2.58

blood creatinine increased ROR = 7.74) and a lower AE signal than the other drugs in the blood and lymphatic systems (leukopenia ROR = 5.34). Ribociclib had a lower AE signal intensity in the blood and lymphatic system than palbociclib (leukopenia ROR = 7.55); however

among hepatic AE

ribociclib had the highest signal intensity of increased gamma-glutamyltransferase (ROR = 4.05). In rare severe hepatic systemic AE

abemaciclib had the strongest signal in hepatic failure (ROR = 3.50) and drug-induced liver injury (ROR = 4.68). Erythema multiforme was a newly identified signal in the abemaciclib reports (ROR = 3.06).

Conclusion:

The safety profile of CDK4/6 inhibitors varies. Analysis of the FAERS database revealed hematologic and lymphatic system toxicities for palbociclib and ribociclib and gastrointestinal and hepatorenal toxicities f

or abemaciclib. Erythema multiforme was found as a novel severe AE for abemaciclib. Individualized drug selection and monitoring of AE based on the patient’s physiological status and AE are needed during treatment.

关键词

Keywords

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