ICH-M3(R2)-中文翻译版

1ICHM3R22009611ICHICHICH2M3R2M31996117M3ICH1997716M3R1≥ICH2000119M3R2M3R12008715M3R22008718M3R2M3R2ICH20096113ICH2009611ICHICHICH11.11.21.31.41.523455.15.2677.17.2Ⅲ7.389101111.111.2≥411.311.41213141516171819205AUCCmaxEUGLPHCGHIVICHi.v.MFDMTDNOAELPETPKPDSARsiRNARNAWOCBP611.13R//ICH1.21.3Ⅲ··71ICHS6ICHM3R2ⅢHIV·siRNAⅢICH1.4/Ⅲ、。ⅢⅢICHE82·1.58MTDMTDⅢMFD1≥Ⅲ34·1000mg/kgdⅠ·1000mg/kgd101g/d102000mg/kgdMFD·2000mg/kgdMFD50[ⅢAUC1]50Ⅲ1000mg/kgdMFDMTD50≥MFDMTDⅢ1000mg/kgd9·1000mg/kgMFDⅢ101.MTD2.3.MFD3.50*101g/dⅢ。2000mg/kgMFD*1.51.102ICHS7A5PDICHS7AS7B56·[Ⅲ]ⅢGLP3ICHS3A,7PKⅢ10%10mg·4ⅢMTD1189GLPGLP·7Ⅲ·1.5GLP·511.5/·5.12126961·112≤22a2a2~6bb66bc9bcda3c214b·3333ⅢⅢ33c.·12d.666lⅢl6ll5.22·231332≤2112~1331~36636c9cd1cd6/NOAEL5.17Ⅲ·37·/PKPDPETⅢⅢ14·5335·ⅢPD32713100µgⅢPETⅢPKⅢ5100µg500µgPET··1Ⅲ33100µg·72ⅢⅢ3ⅢPK15Ⅲ1a·7334514PKPD2AUC2NOAEL≥NOAEL[5]163ab/1≤100µg≤NOAEL1/100≤1/100i.v.mg/kgmg/m2100µg/[]cdi.v.mg/kgmg/m21000SARPETPK2≤500µg56≤100µgNOAEL1/1001/100100µg/[]7i.v.mg/kgmg/m21000SARPETPK173NOAEL1/2/[]2cMTDMFD1.5AmesAmes414MTDNOAELMFDAUCNOAELAUC1/50(PKmg/m2)/[]22AUCAmesAmes18PDAUC1/10NOAELAUC1/2MTD514MTDNOAEL1/50mg/m2/[]2MTDMFD1.5n=3AmesAmes19NOAELAUCNOAELAUC1/2e2NOAEL3NOAEL3aGLPb.10c.2101453142d14100e.AUC208ⅡAUCCmax7、Ⅱ①”9ⅡⅡ④“1010①①10Ⅱ7、10ICHS1A11①”21①Ⅱ③①11311.12311.2①1211.3WOCBP/ⅡWOCBPICHWOCBPWOCBPHCGβ3Ⅱ①22ICH-WOCBP2WOCBPWOCBP”-”4WOCBP15035WOCBPWOCBP①WOCBPWOCBPICH2WOCBPⅡWOCBP3ICH3WOCBP3102311.4310”12①””””1①Ⅱ-Ⅱ①”PK1~3””①③①。③2412612③Ⅱ13ICHS814”14Ⅲ①”/①”①①①①/①25615②Ⅱ/ⅠⅢ”PK/PD/①①②Ⅱ”。16①①ICHQ3AQ3B1213①Ⅱ2617、③[]①Ⅱ”①”Ⅱ3Ⅱ1ⅡⅡ①Ⅱ9090Ⅱ”Ⅱ”PK27”①①”ⅡWOCBP①-①-”--18Ⅱ191AUC③③②CmaxAUC223151631%284-6”GLP517%/WOCBP0.1%/”150WOCBP30.5%6Ⅱ①①201.ICHS6Guideline:PreclinicalSafetyEvaluationforBiotechnological-DerivedPharmaceuticals;July1997.2.ICHE8Guideline:GeneralConsiderationsforClinicalTrials;July1997.3.ICHS5(R2)Guideline:DetectionofToxicitytoReproductionforMedicinalProductsandToxicitytoMaleFertility;June1993.4.ICHS1C(R2)Guideline:DoseSelectionforCarcinogenicityStudiesofPharmaceuticals;March2008.5.ICHS7AGuideline:SafetyPharmacologyStudiesforHumanPharmaceuticals;November2000.6.ICHS7BGuideline:TheNonclinicalEvaluationofthePotentialforDelayedVentricularRepolarization(QTIntervalProlongation)ByHumanPharmaceuticals;May2005.7.ICHS3AGuideline:NoteforGuidanceonToxicokinetics:TheAssessmentof29SystemicExposureinToxicityStudies;October1994.8.NationalCentrefortheReplacement,RefinementandReductionofAnimalsinResearch.ChallengingRequirementsforAcuteToxicityStudies:WorkshopReport;May2007.9.RobinsonS,DelongeasJL,DonaldE,DreherD,FestagM,KervynSetal.AEuropeanpharmaceuticalcompanyinitiativechallengingtheregulatoryrequirementforacutetoxicitystudiesinpharmaceuticaldrugdevelopment.RegulToxicolPharmacol2008;50:345-352.10.ICHS2BGuideline:Genotoxicity:AStandardBatteryforGenotoxicityTestingforPharmaceuticals;July1997.11.ICHS1AGuideline:GuidelineontheNeedforCarcinogenicityStudiesofPharmaceuticals;November1995.12.ICHQ3A(R2)Guideline:ImpuritiesinNewDrugSubstances;October2006.13.ICHQ3B(R2)Guideline:ImpuritiesinNewDrugProducts;June2006.14.ICHS8Guideline:ImmunotoxicityStudiesforHumanPharmaceuticals;September2005.15.SakaiT,TakahashiM,MitsumoriK,YasuharaK,KawashimaK,MayaharaHetal.Collaborativeworktoevaluatetoxicityonmalereproductiveorgansby2-weekrepeated-dosetoxicitystudiesinrats.Overviewofthestudies.JToxicolSci2000;25:1-21.16.SanbuisshoA,YoshidaM,HisadaS,SagamiF,KudoS,KumazawaTetal.Collaborativeworkonevaluationofovariantoxicitybyrepeated-doseandfertilitystudiesinfemalerats.JToxicolSci2009;34:1-22.