Matsumoto Kiyoka, Nakao Satoshi, Hasegawa Shiori, Matsui Toshinobu, Shimada Kazuyo, Mukai Ririka, Tanaka Mizuki, Uranishi Hiroaki, Nakamura Mitsuhiro
Laboratory of Drug Informatics, Gifu Pharmaceutical University, Gifu, Japan.
Department of Pharmacy, Kobe City Medical Center General Hospital, Kobe, Japan.
SAGE Open Med. 2020 May 6;8:2050312120918264. doi: 10.1177/2050312120918264. eCollection 2020.
Drug-induced interstitial lung disease occurs when exposure to a drug causes inflammation and, eventually, fibrosis of the lung interstitium. Drug-induced interstitial lung disease is associated with substantial morbidity and mortality. The aim of this retrospective study was to obtain new information on the time-to-onset profiles of drug-induced interstitial lung disease by consideration of other associated clinical factors using the Japanese Adverse Drug Event Report database.
We identified and analyzed reports of drug-induced interstitial lung disease between 2004 and 2018 from the Japanese Adverse Drug Event Report database. The reporting odds ratio and 95% confidence interval was used to detect the signal for each drug-induced interstitial lung disease incidence. We evaluated the time-to-onset profile of drug-induced interstitial lung disease and used the applied association rule mining technique to uncover undetected relationships, such as possible risk factors.
The reporting odds ratios (95% confidence intervals) of drug-induced interstitial lung disease due to temsirolimus, gefitinib, sho-saiko-to, sai-rei-to, osimertinib, amiodarone, alectinib, erlotinib, everolimus, and bicalutamide were 18.3 (15.6-21.3), 17.8 (16.5-19.2), 16.3 (11.8-22.4), 14.5 (11.7-18.2), 12.5 (10.7-14.7), 10.9 (9.9-11.9), 10.6 (8.1-13.9), 9.6 (8.8-10.4), 9.4 (8.7-10.0), and 9.2 (7.9-10.6), respectively. The median durations (day (interquartile range)) for drug-induced interstitial lung disease were as follows: amiodarone (123.0 (27.0-400.5)), methotrexate (145.5 (67.8-475.8)), fluorouracil (86.0 (35.5-181.3)), gemcitabine (53.0 (20.0-83.0)), paclitaxel (52.0 (28.5-77.5)), docetaxel (47.0 (18.8-78.3)), bleomycin (92.0 (38.0-130.5)), oxaliplatin (45.0 (11.0-180.0)), nivolumab (56.0 (21.0-135.0)), gefitinib (24.0 (11.0-55.0)), erlotinib (21.0 (9.0-49.0)), temsirolimus (38.0 (14.0-68.5)), everolimus (56.0 (35.0-90.0)), osimertinib (51.5 (21.0-84.8)), alectinib (78.5 (44.3-145.8)), bicalutamide (50.0 (28.0-147.0)), pegylated interferon-2α (140.0 (75.8-233.0)), sai-rei-to (35.0 (20.0-54.5)), and sho-saiko-to (33.0 (13.5-74.0)) days. Association rule mining suggested that the risk of drug-induced interstitial lung disease was increased by a combination of amiodarone or sho-saiko-to and aging.
Our results showed that patients who receive gefitinib or erlotinib should be closely monitored for the development of drug-induced interstitial lung disease within a short duration (4 weeks). In addition, elderly people who receive amiodarone or sho-saiko-to should be carefully monitored for the development of drug-induced interstitial lung disease.
药物性间质性肺病是指接触某种药物导致肺部间质发生炎症并最终纤维化。药物性间质性肺病与较高的发病率和死亡率相关。这项回顾性研究的目的是通过使用日本药品不良反应报告数据库并考虑其他相关临床因素，获取有关药物性间质性肺病发病时间概况的新信息。
我们从日本药品不良反应报告数据库中识别并分析了2004年至2018年期间药物性间质性肺病的报告。报告比值比和95%置信区间用于检测每种药物性间质性肺病发病率的信号。我们评估了药物性间质性肺病的发病时间概况，并使用应用关联规则挖掘技术来发现未被检测到的关系，如可能的危险因素。
替西罗莫司、吉非替尼、小柴胡汤、柴苓汤、奥希替尼、胺碘酮、阿来替尼、厄洛替尼、依维莫司和比卡鲁胺所致药物性间质性肺病的报告比值比（95%置信区间）分别为18.3（15.6 - 21.3）、17.8（16.5 - 19.2）、16.3（11.8 - 22.4）、14.5（11.7 - 18.2）、12.5（10.7 - 14.7）、10.9（9.9 - 11.9）、10.6（8.1 - 13.9）、9.6（8.8 - 10.4）、9.4（8.7 - 10.0）和9.2（7.9 - 10.6）。药物性间质性肺病的中位病程（天（四分位间距））如下：胺碘酮（123.0（27.0 - 400.5））、甲氨蝶呤（145.5（67.8 - 475.8））、氟尿嘧啶（86.0（35.5 - 181.3））、吉西他滨（53.0（20.0 - 83.0））、紫杉醇（52.0（28.5 - 77.5））、多西他赛（47.0（18.8 - 78.3））、博来霉素（92.0（38.0 - 130.5））、奥沙利铂（45.0（11.0 - 180.0））、纳武单抗（56.0（21.0 - 135.0））、吉非替尼（24.0（11.0 - 55.0））、厄洛替尼（21.0（9.0 - 49.0））、替西罗莫司（38.0（14.0 - 68.5））、依维莫司（56.0（35.0 - 90.0））、奥希替尼（51.5（21.0 - 84.8））、阿来替尼（78.5（44.3 - 145.8））、比卡鲁胺（50.0（28.0 - 147.0））聚乙二醇干扰素 - 2α（140.0（75.8 - 233.0））、柴苓汤（35.0（20.0 - 54.5））和小柴胡汤（33.0（13.5 - 74.0））天。关联规则挖掘表明，胺碘酮或小柴胡汤与衰老共同作用会增加药物性间质性肺病的风险。
我们的结果表明，接受吉非替尼或厄洛替尼治疗的患者应在短时间内（4周）密切监测是否发生药物性间质性肺病。此外，接受胺碘酮或小柴胡汤治疗的老年人应仔细监测是否发生药物性间质性肺病。
