奥希替尼上市后安全信号的数据挖掘与分析
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摘要
目的:挖掘奥希替尼不良事件(ADEs)信号,为其临床用药安全提供参考。方法:采用报告比值比法(ROR)和贝叶斯判别可信区间递进神经网络法(BCPNN)对美国不良事件报告系统(FAERS)中2015年11月-2018年6月报告数≥3的奥希替尼相关ADEs报告进行数据挖掘和信号检测。结果与结论:共挖掘到奥希替尼相关ADEs报告2 044份,其中涉及的女性患者(1 285例)多于男性(615例);报道年龄以45～64岁(228例)、65～74岁(241例)、≥75岁(248例)为主;上报人员以医师(887例)最多。ROR法和BCPNN法分别挖掘到奥希替尼ADEs信号63、57个,后者所得信号均与前者重叠。所得信号包含药品说明书已记载的皮肤毒性(皮炎、皮疹、皮肤干燥、脆甲、指甲功能异常、甲沟炎)、胃肠道反应(食欲减退、腹泻、口腔黏膜炎)、呼吸系统疾病(间质性肺炎、非感染性肺炎)、血液系统疾病(血小板计数降低、白细胞减少、中性粒细胞计数减少)、血管事件(肺栓塞、深静脉血栓)、QTc间期延长等[ROR值为2.04～56.70,信息分数(IC)值为0.97～4.43],以及药品说明书未提及的新的可疑信号如肝损害、脑梗死、低钠血症、房颤、肾损害、脱水、味觉障碍等(ROR值为2.06～161.74,IC值为1.00～4.58)。临床在使用奥希替尼的过程中,除密切关注指(趾)甲毒性、间质性肺炎、QTc间期延长等已知的安全问题外,也应警惕肝损害等潜在ADEs的发生,以保证用药安全。
OBJECTIVE:To mine the signals of osimertinib adverse drug event(ADEs)and to provide reference for clinical drug safety. METHODS: By reporting odd ratio(ROR) and Bayesian confidence propagation neural network(BCPNN)algorithms,data mining and signal detection were carried out on osimertinib-related ADEs reports with case number ≥3 reported by American Adverse Event Reporting System(FAERS)from Nov. 2015 to Jun. 2018. RESULTS & CONCLUSIONS:A total of 2044 osimertinib-related ADEs were found,among which the female(1 285 cases)was more than the male(615 cases),mainly aged 45-64 years(228 cases),65-74 years(241 cases),≥75 years(248 cases);most of reporters were physicians(887 cases). A total of 63 and 57 osimertinib ADEs signals were mined by ROR and BCPNN methods,and the latter signals overlapped with the former. The obtained signals included skin toxicity(dermatitis acneiform, rash, dry skin, onychoclasis, nail disorder,paronychia),gastrointestinal tract reaction(decreased appetite,diarrhea,stomatitis),respiratory diseases(interstitial pneumonia,pneumonia),hematological diseases(platelet count decreased,white blood cell count decreased,neutrophil count decreased),vascular events(pulmonary embolism,deep vein thrombosis),electrocardiogram QT prolonged(RORs were 2.04-56.70,ICs were0.97-4.43),all of which had been recorded in drug instructions;obtained signals also included new suspicious signals not indicated in the drug instructions, such as liver damage, cerebral infarction, hyponatremia, atrial fibrillation, renal impairment,dehydration,dysgeusia,and so on(RORs were 2.06-161.74,ICs were 1.00-4.58). In clinical use of osimertinib,besides paying close attention to known safety problems such as nail toxicity of finger(toe)and rash,interstitial pneumonia,electrocardiogram QT prolonged,we should also be alert to the occurrence of potential ADEs such as liver damage to ensure drug safety.
OBJECTIVE:To mine the signals of osimertinib adverse drug event(ADEs)and to provide reference for clinical drug safety. METHODS: By reporting odd ratio(ROR) and Bayesian confidence propagation neural network(BCPNN)algorithms,data mining and signal detection were carried out on osimertinib-related ADEs reports with case number ≥3 reported by American Adverse Event Reporting System(FAERS)from Nov. 2015 to Jun. 2018. RESULTS & CONCLUSIONS:A total of 2044 osimertinib-related ADEs were found,among which the female(1 285 cases)was more than the male(615 cases),mainly aged 45-64 years(228 cases),65-74 years(241 cases),≥75 years(248 cases);most of reporters were physicians(887 cases). A total of 63 and 57 osimertinib ADEs signals were mined by ROR and BCPNN methods,and the latter signals overlapped with the former. The obtained signals included skin toxicity(dermatitis acneiform, rash, dry skin, onychoclasis, nail disorder,paronychia),gastrointestinal tract reaction(decreased appetite,diarrhea,stomatitis),respiratory diseases(interstitial pneumonia,pneumonia),hematological diseases(platelet count decreased,white blood cell count decreased,neutrophil count decreased),vascular events(pulmonary embolism,deep vein thrombosis),electrocardiogram QT prolonged(RORs were 2.04-56.70,ICs were0.97-4.43),all of which had been recorded in drug instructions;obtained signals also included new suspicious signals not indicated in the drug instructions, such as liver damage, cerebral infarction, hyponatremia, atrial fibrillation, renal impairment,dehydration,dysgeusia,and so on(RORs were 2.06-161.74,ICs were 1.00-4.58). In clinical use of osimertinib,besides paying close attention to known safety problems such as nail toxicity of finger(toe)and rash,interstitial pneumonia,electrocardiogram QT prolonged,we should also be alert to the occurrence of potential ADEs such as liver damage to ensure drug safety.
引文
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[20]GOSS G,TSAI CM,SHEPHERD FA,et al.Osimertinib for pretreated EGFR Thr790Met-positive advanced nonsmall-cell lung cancer(AURA2):a multicentre,open-label,single-arm,phase 2 study[J].Lancet Oncol,2016,17(12):1643-1652.
[21]YOSHIDA H,KIM YH.Successful osimertinib rechallenge after severe osimertinib-induced hepatotoxicity[J].JThorac Oncol,2017.DOI:10.1016/j.jtho.2017.01.026.
[22]HIRABAYASHI R,FUJIMOTO D,SATSUMA Y,et al.Successful oral desensitization with osimertinib following osimertinib-induced fever and hepatotoxicity:a case report[J].Invest New Drugs,2018,36(5):952-954.
[23]王璇.酪氨酸激酶抑制剂克唑替尼肝毒性的相关研究[D].重庆:第三军医大学,2016.
[24]US Food and Drug Administration.TagrissoTM(osimertinib)tablet,for oral use:US prescribing information[EB/OL].(2015-11-13)[2018-10-12].http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf.
[25]NONAGASE Y,TAKEDA M,TANAKA K,et al.Treatment of EGFR mutation-positive non-small cell lung cancer complicated by Trousseau syndrome with gefitinib followed by osimertinib:a case report[J].Oncotarget,2018,9(50):29532-29535.
[26]SORIA JC,OHE Y,VANSTEENKISTE J,et al.Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer[J].N Engl J Med,2018,378(2):113-125.
[27]KIM SJ,PARK JH,LEE MJ,et al.Clues to occult cancer in patients with ischemic stroke[J].PLoS One,2012.DOI:10.1371/journal.pone.0044959.
[28]HSU F,DE CALUWE A,ANDERSON D,et al.EGFRmutation status on brain metastases from non-small cell lung cancer[J].Lung Cancer,2016.DOI:10.1016/j.lungcan.2016.04.004.
[2]邹晓宏,张翠英.第三代EGFR-TKI奥希替尼治疗NSCLC研究新进展[J].内蒙古医学杂志,2018,50(3):293-295.
[3]SHIAU CJ,BABWAN JP,DA CUNHA SANTOS G,et al.Sample features associated with success rates in population based EGFR mutation testing[J].J Thorac Oncol,2014,9(7):947-956.
[4]YU HA,ARCILA ME,REKHTMAN N,et al.Analysis of tumor specimens at the time of acquired resistance to EG-FR-TKI therapy in 155 patients with EGFR mutant lung cancers[J].Clin Cancer Res,2013,19(8):2240-2247.
[5]J?NNE PA,YANG JC,KIM DW,et al.AZD9291 in EG-FR inhibitor resistant non-small-cell lung cancer[J].NEngl J Med,2015,372(18):1689-1699.
[6]YANG JC,AHN MJ,KIN DW,et al.Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer:AURA study phaseⅡextension componen[J].J Clin Oncol,2017,35(12):1288-1296.
[7]唐学文,田晓江,董志,等.左氧氟沙星、莫西沙星和环丙沙星上市后安全警戒信号的挖掘与评价:基于真实世界不良反应研究[J].中国新药杂志,2018,27(5):596-692.
[8]任经天,王胜锋,侯永芳,等.常用药品不良反应信号检测方法比较研究[J].中国药物警戒,2011,8(6):356-359.
[9]李婵娟,王素珍,王陵,等.基于模拟数据库的药品不良事件信号检测方法比较[J].中国卫生统计,2009,26(2):124-127.
[10]潘建玲,刘照元,陈婕,等.利妥昔单抗不良事件信号挖掘与分析[J].中国药学杂志,2016,51(22):1976-1981.
[11]李苑雅,张艳,沈爱宗.基于自发呈报系统药品不良反应信号检测方法的研究进展[J].安徽医药,2015,19(7):1233-1236.
[12]US Food and Drug Administration.Medical review for osimertinib[EB/OL].(2015-12-221)[2018-12-10].http://www.acce-ssdata.fda.gov/drugsatfda_docs/nda/2014/202-293Origls000MedR.pdf.
[13]MAMESAYA N,KENMOTSU H,KATSUMATA M,et al.Osimertinib-induced interstitial lung disease after treatment with anti-PD1 antibody[J].Invest New Drugs,2017,35(1):105-107.
[14]AHN MJ,YANG J,YU H,et al.136O osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer:results from the TATTON phaseⅠb trial[J].J Thorac Oncol,2016.DOI:10.1016/S1556-0864(16)30246-5.
[15]KOMADA F.Analysis of time-to-onset of interstitial lung disease after the administration of small molecule molecularly-targeted drugs[J].Yakugaku Zasshi,2018,138(2):229-235.
[16]MIYAUCHI E,ICHINOSE M,INOUE A.Successful osimertinib rechallenge in a patient with T790M-mutant non-small cell lung cancerafter osimertinib-induced interstitial lung disease[J].J Thorac Oncol,2017.DOI:10.1016/j.jtho.2017.01.027.
[17]WYNN TA.Integrating mechanisms of pulmonary fibrosis[J].J Exp Med,2011,208(7):1339-1350.
[18]European Medicines Agency.Summary of the risk management plan(RMP)for Tagrisso(osimertinib)[EB/OL].(2017-10-13)[2018-11-10].http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004124/WC500202022.pdf.
[19]SCHIEFER M,HENDRIKS LEL,DINH T,et al.Current perspective:osimertinib-induced QT prolongation:new drugs with new side-effects need careful patient monitoring[J].Eur J Cancer,2018.DOI:10.1016/j.ejca.2017.12.011.
[20]GOSS G,TSAI CM,SHEPHERD FA,et al.Osimertinib for pretreated EGFR Thr790Met-positive advanced nonsmall-cell lung cancer(AURA2):a multicentre,open-label,single-arm,phase 2 study[J].Lancet Oncol,2016,17(12):1643-1652.
[21]YOSHIDA H,KIM YH.Successful osimertinib rechallenge after severe osimertinib-induced hepatotoxicity[J].JThorac Oncol,2017.DOI:10.1016/j.jtho.2017.01.026.
[22]HIRABAYASHI R,FUJIMOTO D,SATSUMA Y,et al.Successful oral desensitization with osimertinib following osimertinib-induced fever and hepatotoxicity:a case report[J].Invest New Drugs,2018,36(5):952-954.
[23]王璇.酪氨酸激酶抑制剂克唑替尼肝毒性的相关研究[D].重庆:第三军医大学,2016.
[24]US Food and Drug Administration.TagrissoTM(osimertinib)tablet,for oral use:US prescribing information[EB/OL].(2015-11-13)[2018-10-12].http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf.
[25]NONAGASE Y,TAKEDA M,TANAKA K,et al.Treatment of EGFR mutation-positive non-small cell lung cancer complicated by Trousseau syndrome with gefitinib followed by osimertinib:a case report[J].Oncotarget,2018,9(50):29532-29535.
[26]SORIA JC,OHE Y,VANSTEENKISTE J,et al.Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer[J].N Engl J Med,2018,378(2):113-125.
[27]KIM SJ,PARK JH,LEE MJ,et al.Clues to occult cancer in patients with ischemic stroke[J].PLoS One,2012.DOI:10.1371/journal.pone.0044959.
[28]HSU F,DE CALUWE A,ANDERSON D,et al.EGFRmutation status on brain metastases from non-small cell lung cancer[J].Lung Cancer,2016.DOI:10.1016/j.lungcan.2016.04.004.