肺癌靶向药特罗凯、凯美纳、易瑞沙三药比较

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/IVptsLinktosupportinginfoAlldatatobeupdated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