帕洛诺司琼-当代肿瘤化疗止吐药物的基石

帕洛诺司琼当代肿瘤化疗止吐药物的基石,内容,化疗所致恶心/呕吐(CINV)的概述化疗药物的致吐风险分类止吐药物的概述第二代5-HT3受体抑制剂帕洛诺司琼有关帕洛诺司琼的若干问题总结,化疗所致恶心/呕吐(CINV)的概述,迟发性恶心/呕吐的自然病程,KrisMJetal.JClinOncol.1985;3:1379-84.,0,10,20,30,40,50,60,70,80,90,0-24,24-48,48-72,72-96,96-120,Hoursaftercisplatin,Percentwithnauseaor,vomiting,Vomiting,Nausea,医生的预测vs.患者的实际感受,高度致吐化疗,中度致吐化疗,GrunbergS.etal.Cancer2004;100:2261,相关术语的定义,Vomiting(呕吐)expulsionofstomachcontentsNausea(恶心)subjectivefeelingofimminentvomitingCompleteResponse(完全缓解)novomitingorrescuemedicationCompleteControl(完全控制)novomiting,rescuemedicationorsignificantnauseaTotalControl(总体控制)novomiting,rescuemedicationornausea,化疗药物的致吐风险分类,化疗药物致吐风险分类,CINV的其它危险因素,AgemenHistoryoflightalcoholuseHistoryofvomitingwithpriorexposuretochemotherapeuticagentsOtherrisksHistoryofmotionsicknessHistoryofnauseaorvomitingduringpregnancyHistoryofanxiety,ASHP.AmJHealthSystPharm.1999:56:729-764;BalfourandGoa.Drugs.1997:54:273-298.,止吐药物的概述,第二代5-HT3受体抑制剂帕洛诺司琼,Azabicyclo-hexahydro-oxo-benzdeisoquinolinederivative,HCI,H,O,H,N,N,Molecularwt:332.87,帕洛诺司琼的化学结构,Amajorstructuraldifferencevsserotoninwouldbeexpectedtoimpactbindingatthe5-HT3receptor,5-羟色胺和5-HT3受体抑制剂的化学结构,*Log-scale.Invitrodata;clinicalsignificancehasnotbeenestablished.Palonosetronhasabindingaffinityatleast30-foldhigherthanother5-HT3receptorantagonists.,5-HT3受体抑制剂的药代动力学,帕洛诺司琼的优势,半衰期长与5-HT3受体的亲和力强通过额外结合变构位点(allostericsite)，导致对5-HT3受体的持续抑制(AnesthAnalg2008;107:469)造成5-HT3受体内陷从而丧失功能(EurJPharmacol2010;626:193),注册III期临床,GrallaR,etal.AnnOncol2003;14:1570-7EisenbergP,etal.Cancer2003;98:2473-82AaproMS,etal.AnnOncol2006;17:1441-9,相关毒性比较(1237patients),1%incidenceofcardiovascularevents(QTprolongation),疗效比较(帕洛诺司琼vs.第1代药物),荟萃分析,BotrelTE,etal.SupportCareCancer2010,有关恶心和呕吐发作的分析,QOL比较(帕洛诺司琼vs.第1代药物),NIDL(NoImpactonDailyLife),DeckerM,etal.JSupportOncol2006;4:35,FLIE(FunctionalLivingIndex-Emesis),DeckerM,etal.JSupportOncol2006;4:35,有关帕洛诺司琼的若干问题,问题1：帕洛诺司琼的最佳剂量？,0.25mg(从经济学角度),问题2：何类止吐药物能够有效解救治疗延迟性/暴发性呕吐？,第1代5-HT3受体抑制剂：不太可能多巴胺受体抑制剂：有可能帕洛诺司琼：很有可能,非随机、历史对照II期试验,MussoM,etal.SupportCareCancer2009;17:205,解救治疗结果,MussoM,etal.SupportCareCancer2009;17:205,问题3：帕洛诺司琼可否用于对抗多天化疗所致的CINV?,可以,March2008,MultinationalAssociationofSupportiveCareinCancer,COMMITTEEVII:,Guidelineforpatientsreceivingmultiple-daycisplatin:Patientsreceivingmultiple-daycisplatinshouldreceivea5-HT3antagonistplusdexamethasoneforacutenauseaandvomitinganddexamethasonefordelayednauseaandvomiting.Palonosetronisa5HT3option(0.25mgIVdays1,3,and5).MASCClevelofconfidence:HighMASCClevelofconsensus:HighASCOlevelofevidence:IIASCOgradeofrecommendation:A,Noguidelinewasfelttobeappropriateforrescueantiemesisorhigh-dose(i.e.transplant)chemotherapy,Note:,问题4：帕洛诺司琼联合阿瑞匹坦可否增效？,可以,II期随机试验,ArmAPalod1+Dexd14+Apred1-3(n=29),ArmCPalod1+Dexd14(n=16),ArmBPalod1+Dexd14+Apred1(n=30),PatientsonHEC(n=75),HerringtonJD,etal.Cancer2008;112:2080,Palo:palonosetronApre:aprepitantDex:dexamethasone,图示,问题5：阿瑞匹坦可否彻底取代5-HT3受体抑制剂？,不可,Patientsoncisplatin(n=351),Gran+dexd1/placebod25(n=90),Gran+dex+apred1/apred25(n=86),Apred0/apre+dexd1/apred25(n=89),Apre+dexd1/apred25(n=86),III期随机试验,CamposD,etal.JClinOncol2001;19:1759,Gran:granisetronApre:aprepitantDex:dexamethasone,结果,问题6：在帕洛诺司琼/阿瑞匹坦基础上，是否可以联合其他药物进一步对抗CINV?,有可能,奥氮平(olanzapine),抗精神病药物抑制多种神经递质多巴胺5-羟色胺儿茶酚胺乙酰胆碱组胺,不同药物组合时对恶心的完全缓解率,SaitoM,etal.LancetOncol2009;10:115,GrotoT,etal.JSupportOncol2006;4:403,NavariRM,