治疗晚期NSCLC3个EGFR-TKI药物比较分析目录化学结构药代动力学临床疗效其他方面的比较药物结构与分子量/分子式:通用名称厄洛替尼(Erlotinib)埃克替尼(Icotinib)吉非替尼(Gefitinat)商品名特罗凯凯美纳易瑞沙生产厂家罗氏贝达阿斯利康分子式C22H23N3O4HClC22H21N3O4HClC22H24ClFN4O3分子量429.90427.88446.90上市时间2004年2011年2003年MIMSannual中国药品手册年刊中国版2011/2012第15版P421,P1045,P860.NNHNoNNNHNooClFooooNNHN三药有相同的喹唑啉母环,埃克替尼与厄洛替尼的差别仅在侧链的开环与闭环,厄洛替尼于2004年上市,埃克替尼于2011年上市。目录化学结构药代动力学临床疗效其他方面的比较分子水平:EGFR激酶抑制62nM(25ng/ml)100%抑制细胞水平:EGFR激酶抑制250nM(100ng/ml)100%抑制厄洛替尼欧美人体稳态血药浓度(150mgQd):2500nM(1000ng/ml)埃克替尼中国人体稳态血药浓度(125mgTid):2500nM(1000ng/ml)吉非替尼欧美人体稳态血药浓度(300mgQd):750nM(300ng/ml)EGFR激酶的抑制水平&人体血药浓度:血药浓度与药效的关系呈线性相关,随着血药浓度增加,药效也逐渐增强1达到同样血药浓度厄洛替尼剂量为150mg,埃克替尼为375mg,吉非替尼为1000mg倍,每天仅需服药一次,埃克替尼每天需服用三次。推荐剂量下,厄洛替尼治疗浓度是吉非替尼的4倍,并优于埃克替尼,谷底浓度也最高。埃克替尼峰谷浓度波动大,血药浓度不稳定厄洛替尼2,4埃克替尼1,2吉非替尼2,3给药方法150mgqd125mgtid250mgqd达峰时间(小时)40.5-43-7半衰期(小时)36.2641-48峰/谷浓度(ng/ml)1737/11682050/995378/330达稳态时间(天)7-87-117-10血浆蛋白结合率(%)9398.590蓄积效应无无有主要代谢途径CYP3A4CYP2C19/CYP3A4CYP3A4生物利用度的影响:厄洛替尼VS吉非替尼12343543566547678厄洛替尼较吉非替尼生物利用度高(F值)时量曲线下面积(AUC)是表示药物吸收入血液循环量的最好指标。厄洛替尼的AUC是吉非替尼的5倍N.P.vanErpetal.CancerTreatmentReviews.2009;35:692–706HidalgoM,etal.JClinOncol2001;19:3267–79RansonM,etal.JClinOncol2002;20:2240–50Cmax(ng/mL)AUC0–24(ng·hour/L)Erlotinib150mg/dayGefitinib225mg/dayGefitinib525mg/dayGefitinib700mg/day2,5002,0001,5001,000500045,00040,00035,00030,00025,00020,00015,00010,0005,0000药物动力学比较(每日剂量)•Cmax和AUC剂量比•重复每日给药并不影响药物蓄积•厄洛替尼在每日口服150mg时有最高血浆浓度150mg厄洛替尼与700mg吉非替尼有相同药物动力学IC50值比较厄洛替尼IC50值最低,诱导能力最强,作用最好1、不同水平厄洛替尼#埃克替尼吉非替尼#分子水平(IC50)2.5nM5nM27nM细胞水平(IC50)20nM50nM80-90nM细胞生长(IC50)1µM1µM8.8µM动物水平(60mg/kg)56%52%38%厄洛替尼服用剂量少,人体稳态血药浓度高,有助于获得更好的临床疗效推荐剂量下厄洛替尼治疗浓度是吉非替尼的4倍,并优于埃克替尼厄洛替尼、吉非替尼半衰期是埃克替尼的6倍,每天仅需服药一次埃克替尼每天需服用三次厄洛替尼较吉非替尼生物利用度高厄洛替尼的AUC是吉非替尼的5倍150mg厄洛替尼与700mg吉非替尼有相同药物动力学厄洛替尼IC50值最低,诱导能力最强,疗效作用更好药代动力学小结目录化学结构药代动力学临床疗效其他方面的比较临床研究的比较厄洛替尼一线,二线,维持等研究多,埃克替尼仅有二线ICOGEN研究,且目前该研究尚未全文发表,亦无第三方评价,资料可靠性无法保证!厄洛替尼埃克替尼吉非替尼一线治疗OPTIMALIPASSEURTACNEJ002TORCHWJTOG3405FIELTFirst-SIGNALCALGB30406SLCG维持治疗SATURNINFORM二线治疗BR.21ICOGENISELTITANINTERESTV-15-32在突变人群厄洛替尼和吉非替尼的比较TarcevaistheonlyEGFRTKItoextendPFSbeyond12monthsinaphaseIIItrialAcrossmajorstudiesinEGFRMut+NSCLC,medianPFSwasconsistentlylongerwithTarcevathanwithgefitinibOnlyTarcevahasproducedamedianPFSof12monthsinaphaseIIItrialAccompanyingtext:MedianPFSforstudiesofEGFRTKIsinEGFRMut+NSCLCIntheOPTIMALstudy,whichwasperformedinChina,TarcevaproducedamedianPFSof13.1months;thisisconsistentwithotherstudiesofTarcevainthisdisease,andgreaterthanthatobservedwithgefitinibRosell,etal.LancetOncol2012;DeGreve,etal.ASCO2011;Rosell,etal.NEJM2009;Janne,etal.JClinOncol2012;Zhou,etal.LancetOncol2011;Mok,etal.NEJM2009;Han,etal.JClinOncol2012;Mitsudomi,etal.LancetOncol2010;Maemondo,etal.NEJM2010TarcevaGefitinib9.71314.113.19.588.410.85.24.66.36.35.35.414MedianPFS(months)1614121086420SLCGCALGB30406OPTIMALIPASSFirst-SIGNALWJTOG3405NEJSG002EURTACEURTACIPASSFirst-SIGNALWJTOG3405OPTIMALNEJSG002Platinum-doubletchemotherapyFIELTFollowingbarshavebeenchanged:TarcevaOPTIMAL,GefitinibFirst-SIGNAL,chemotherapyFirst-SIGNALWJTOG3405:stageIIIB/IVptsLinktosupportinginfoAlldatatobeupdated厄洛替尼vs吉非替尼:一线临床研究厄洛替尼较吉非替尼在一线治疗晚期NSCLC患者上有优势。埃克替尼并无相关一线研究ApooledanalysisshowedthatTarcevaproduceslongestPFSinEGFRMut+Apooledanalysisofdatafromover90publishedstudiesconfirmedthatmedianPFSislongerwithTarcevathanwithgefitinibinEGFRMut+NSCLCAccompanyingtext:MedianPFSfrompooledanalysisofstudieswithEGFRTKIsandchemotherapyinEGFRMut+NSCLCPaz-Ares,etal.ESMO2012Supportinginfo0.050.10.250.51.0HRFavoursEGFRTKI0.190.39TarcevaGefitinibFavourschemoMeta-analysisconfirmslongerPFSwithTarcevavsgefitinibAccompanyingtext:Meta-analysisofPFSin8randomised,controlledstudiesincludingpatientswithEGFRMut+NSCLC(mixedline)Petrelli,etal.ClinLungCancer2012Ameta-analysisofPFSin8randomised,controlledtrials,showedasignificantdifferenceinthebenefitoverchemotherapyprovidedbyTarcevavsgefitinibinEGFRMut+NSCLC(anylineoftherapy)SupportinginfoStatisticallysignificantdifferencebetweentreatmentsMeta-analysisconfirmslongerPFSwithTarcevavsgefitinibSupportinginfoAccompanyingtext:Meta-analysisofPFSin6randomised,controlledstudiesincludingpatientswithEGFRMut+NSCLC(first-line)Gao,etal.IntJCancer20110.260.43FavoursEGFRTKIvschemoHR0.050.10.250.51.0StatisticallysignificantdifferencebetweentreatmentsAmeta-analysisofPFSin6randomised,controlledtrials,showedasignificantdifferenceinthebenefitoverchemotherapyprovidedbyfirst-lineTarcevavsgefitinibinEGFRMut+NSCLCTarcevahasasimilartolerabilityprofiletogefitinibinEGFRMut+NSCLCStudyEGFRTKIRash,%All(grade≥3)Diarrhoea,%All(grade≥3)NEJSG002Gefitinib71(5)34(1)WJTOG30405Gefitinib74(2)47(1)OPTIMALTarceva73(2)25(1)InphaseIIItrialsincludingAsianpatientswithEGFRMut+NSCLC,thetolerabilityprofilesofTarcevaandgefitinibwereverysimilarAccompanyingtext:IncidenceofrashanddiarrhoeainphaseIIIstudiesincludingAsianpatientswithEGFRMut+NSCLC(mixedline)Maemondo,etal.NEnglJMed2010;Mitsudomi,etal.LancetOncol2010;Zhou,etal.LancetOncol2011在二