Shah Devron R, Hart Simon P, Sykes Dominic L
Department of Respiratory Medicine, Castle Hill Hospital, Castle Road, Cottingham, HU16 5JQ, UK.
Drugs Real World Outcomes. 2025 Sep 2. doi: 10.1007/s40801-025-00515-9.
Increasing global frequency of drug-induced interstitial lung disease (ILD) coincides with increasing market introduction of tyrosine kinase inhibitors (TKIs).
The aim was to detect disproportional reporting of TKI-induced ILD in the EudraVigilance post-marketing safety database and to scrutinise the prescribing information of these TKIs.
Data were gathered on the number of total and individual ILD case safety reports for each TKI marketed in the European Union (EU), together with indications and patient demographics. Information was also obtained on numbers of total and ILD reports for all drugs in the entire database, covering the period January 2002 to March 2024. Chi-squared analyses and two measures of disproportionality, the proportional reporting ratio (PRR) and reporting odds ratio (ROR), were used to ascertain the ILD-inducing potential of TKIs, both as a group and with each TKI individually. The latest prescribing information for each TKI was evaluated for ILD-related information.
TKIs were collectively associated with a significantly stronger disproportionality signal for ILD reports compared to all non-TKI drugs (p < 0.001). There was marked variation in the disproportionality of ILD reporting across the 51 TKIs studied. Potential risk factors included male gender (p < 0.001), age 65-85 years (p < 0.001) and an oncological indication (p < 0.001), particularly non-small cell lung cancer (NSCLC). Fatality rates among cases of TKI-induced ILD were 17.4% overall, 22.2% in patients with NSCLC and 11.5% in those with a non-oncological indication. The prescribing information of 11 TKIs lacked any reference to ILD despite a strong signal that indicated their potential association with ILD.
Drug-induced ILD is emerging as an important safety issue, and physicians need to maintain a high index of suspicion of ILD in patients treated with a TKI.
全球范围内药物性间质性肺病（ILD）的发病率不断上升，与此同时酪氨酸激酶抑制剂（TKIs）在市场上的推出也越来越多。
旨在检测欧洲药品不良反应数据库（EudraVigilance）上市后安全性数据库中TKI诱导的ILD的不成比例报告情况，并审查这些TKIs的处方信息。
收集了欧盟市场上销售的每种TKI的ILD病例安全报告总数和各病例报告数量，以及适应症和患者人口统计学信息。还获取了整个数据库中所有药物在2002年1月至2024年3月期间的报告总数和ILD报告数量。采用卡方分析以及两种不成比例性衡量指标，即比例报告率（PRR）和报告比值比（ROR），来确定TKIs作为一个整体以及每种TKI个体诱发ILD的可能性。对每种TKI的最新处方信息进行了ILD相关信息评估。
与所有非TKI药物相比，TKIs总体上与ILD报告的不成比例性信号明显更强（p < 0.001）。在所研究的51种TKIs中，ILD报告的不成比例性存在显著差异。潜在风险因素包括男性（p < 0.001）、65 - 85岁年龄组（p < 0.001）和肿瘤适应症（p < 0.001），尤其是非小细胞肺癌（NSCLC）。TKI诱导的ILD病例总体死亡率为17.4%，NSCLC患者为22.2%，非肿瘤适应症患者为11.5%。尽管有强烈信号表明11种TKIs与ILD存在潜在关联，但它们的处方信息中却未提及任何关于ILD的内容。
药物性ILD正成为一个重要的安全问题，医生在使用TKI治疗的患者中需要对ILD保持高度怀疑。
