Raschi Emanuel, Fusaroli Michele, Ardizzoni Andrea, Poluzzi Elisabetta, De Ponti Fabrizio
Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy.
Medical Oncology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Policlinico S. Orsola-Malpighi, Alma Mater Studiorum - University of Bologna, Bologna, Italy.
Breast Cancer Res Treat. 2021 Feb;186(1):219-227. doi: 10.1007/s10549-020-06001-w. Epub 2020 Nov 5.
We assessed pulmonary toxicity of cyclin-dependent kinase (CDK)4/6 inhibitors by analyzing the publicly available FDA Adverse Event Reporting System (FAERS).
Reports of interstitial lung disease (ILD) were characterized in terms of demographic information, including daily dose, latency, concomitant drugs known to be associated with ILD, and causality assessment (adapted WHO system). Disproportionality analyses were carried out by calculating reporting odds ratios (RORs) with 95% confidence interval (CI), accounting for major confounders, including notoriety and competition biases.
ILD reports (N = 161) represented 2.1% and 0.3% of all reports for abemaciclib and palbocilcib/ribociclib, respectively, with negligible proportion of concomitant pneumotoxic drugs. Increased reporting was found for CDK4/6 inhibitors when compared to other drugs (ROR = 1.50; 95%CI = 1.28-1.74), and abemaciclib vs other anticancer agents (4.70; 3.62-5.98). Sensitivity analyses confirmed a strong and consistent disproportionality for abemaciclib. Higher-than-expected reporting emerged for palbociclib (1.38; 1.07-1.77) and ribociclib (2.39; 1.34-3.92) only when removing Japan reports. ILD occurred at recommended daily doses, with median latency ranging from 50 (abemaciclib) to 253 (ribociclib) days. Causality was highly probable in 55% of abemaciclib cases, probable in 68% of palbociclib cases.
Increased reporting of ILD with CDK4/6 inhibitors calls for further comparative population-based studies to characterize and quantify the actual risk, taking into account drug- and patient-related risk factors. These findings strengthen the role of (a) timely pharmacovigilance to detect post-marketing signals through FAERS and other real-world data, (b) clinicians to assess early, on a case-by-case basis, the potential responsibility of CDK4/6 inhibitors when diagnosing a lung injury.
我们通过分析公开可用的美国食品药品监督管理局不良事件报告系统（FAERS）来评估细胞周期蛋白依赖性激酶（CDK）4/6抑制剂的肺部毒性。
根据人口统计学信息对间质性肺疾病（ILD）报告进行特征分析，包括每日剂量、潜伏期、已知与ILD相关的伴随用药以及因果关系评估（采用世界卫生组织系统）。通过计算报告比值比（ROR）及95%置信区间（CI）进行不成比例分析，并考虑主要混杂因素，包括知名度和竞争偏差。
ILD报告（N = 161）分别占阿贝西利和哌柏西利/瑞博西利所有报告的2.1%和0.3%，伴随肺毒性药物的比例可忽略不计。与其他药物相比，CDK4/6抑制剂的报告增加（ROR = 1.50；95%CI = 1.28 - 1.74），阿贝西利与其他抗癌药物相比（4.70；3.62 - 5.98）。敏感性分析证实阿贝西利存在强烈且一致的不成比例性。仅在去除日本报告后，哌柏西利（1.38；1.07 - 1.77）和瑞博西利（2.39；1.34 - 3.92）出现高于预期的报告发生率。ILD发生在推荐的每日剂量下，中位潜伏期从50天（阿贝西利）到253天（瑞博西利）不等。在55%的阿贝西利病例中因果关系极有可能，在68%的哌柏西利病例中因果关系很可能。
CDK4/6抑制剂导致ILD的报告增加，需要进一步开展基于人群的比较研究，以考虑药物和患者相关风险因素来描述和量化实际风险。这些发现强化了以下作用：（a）通过FAERS和其他真实世界数据进行及时的药物警戒以检测上市后信号；（b）临床医生在诊断肺损伤时逐例早期评估CDK4/6抑制剂的潜在责任。
