新药研发医学知识培训专家讲座

UnitoneTxtADevelopmentofnewdrugs新药研发医学知识培训第1页Newwordsandexpressionacute:acuteinfection（急性感染）,acuteleukemia（急性白血病）chronic:chronicgastritis（慢性胃炎）agonist:stimulatorantagonist:blockeradversereaction（不良反应）:anybadeffectorundesirableeffectcausedbydruguseatnormaldose（正常剂量）新药研发医学知识培训第2页newchemicalentity(新化学实体):newcompoundshowspharmacologicalactivityagainstcertaindisease,whichisalsocalledleadcompound(先导化合物)ordrugcandidate(候选药品)in-vitro（体外）:outsideoforganismsinvivo（体内）:withinawholelivingorganism新药研发医学知识培训第3页1.Whatisanewdrug?Chemicalstructure（化学成份）

Dosageform(剂型）Routeofadministration（给药路径）Indication（适应症）Newdrug新药研发医学知识培训第4页2.Whydoweneednewdrugs?manyincurablediseasesstillawaitconquesttoproducenewdrugsthataresuperiorthanexistingmedicationstheultimategoal:toprovideeffective,accessibleandaffordablemedicinesforall新药研发医学知识培训第5页①Inthepast,drugswereextractedfromplantandanimalsources,butthepurityofdrugswasverylimited.quinine（奎宁）:extractedfromthebarkofcinchona（金鸡纳树皮）,itsantimalarial（抗疟疾）functionwasdiscoveredbytheIndiansinNorthAmerica

3.Evolutionofnewdrug新药研发医学知识培训第6页②From1900chemicallysynthesizeddrugsbecameavailable,thepurityofdrugswereremarkablypromotedwhichincreasedthespecificityofaction.e.g.quininecanbeartificiallysynthesizedin1945Nowadaysmostwesternmedicinesaretotallysynthesizedorsemi-synthesized新药研发医学知识培训第7页③Withthedevelopmentofgeneticengineering（基因工程）moredrugswillbeproducedartificially.

e.g.thefirstgeneticallyengineereddrugisrh-insulin(forthetreatmentofdiabetes)andwasfirstmarketedinAmericain1982.新药研发医学知识培训第8页4.RegulationofdrugdevelopmentTherangeofnovelchemicalentitiesdevelopedhasoccasionallyledtounexpectedtoxicity.Inordertoensurethesafetyandefficacyofnewdrugs,theirdevelopmentmustfollowstatutoryprocedures（法定程序）.新药研发医学知识培训第9页

Thalidomide--------abigtragedy!

ThalidomidewasdevelopedbyaGermanpharmaceuticalcompany.Itwassoldfrom1957to1961inalmost50countriesunderatleast40brandnames.Thalidomidewaschieflysoldandprescribedtopregnantwomen,asanantiemetic(止吐药)tocombatmorningsicknessandasanaidtohelpthemsleep。In1961whenthalidomidewaswithdrawnfromthemarket,morethantenthousanddeformedbabieswereborn.Theysufferedfromphocomelia(海豹肢).

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Developinganewdrugisahighlycomplex,time-consuming,riskyandcostlyprocess.5.Anoverviewofnewdrugdevelopment新药研发医学知识培训第11页complexandtime-consumingNewdrugdevelopmentrequiresmultidisciplinaryeffortsformanyyears,involvingnumerousstepsandmanysophisticatedtechniques0.5-1year3-4years6-8years2-3years新药研发医学知识培训第12页risky:

OnlyaverysmallportionofNCEscanbefinallymarketedasdrugproduct新药研发医学知识培训第13页costly:

Onebillion新药研发医学知识培训第14页6.Developmentofnewdrugs6.1Strategiesfordiscoveringnewchemicalentities①Serendipity:Thenewtherapeuticagentisdiscoveredbychance.e.g.thediscoveryofpenicillin

AlexanderFleming

penicillum新药研发医学知识培训第15页②Molecularroulette（分子轮盘赌）Agreatmanyofnewchemicalstructuresweresynthesizedrandomlyandscreenedbyanimalorin-vitromodelsofhumandiseasetoseeifanyofthenewlyobtainedstructuresprovecertaineffect.Disadvantage:wasteful,dependentonsensitivemodelsforscreening新药研发医学知识培训第16页③Minorstructurechangesinexistingagents

Penicillin，青霉素Penicillin∨Oxacillin，苯唑西林Ampicillin，氨苄西林新药研发医学知识培训第17页Disadvantagesofpenicillin:unstabletoacidunstabletoβ-lactamase(内酰胺酶)littleeffectonGramnegativebacteria（革兰氏阴性菌）新药研发医学知识培训第18页

④Programmedbasicresearchwithsynthesisofspecificchemicalse.g.1Histamie(H2)receptorantagonist(suchasCimetidine西米替丁)forpepticulcerHistaminereceptorscanbeclassifiedintothreeclasses,H1,H2andH3,theydistributeindifferenttissues,andcausedifferenteffectswhenagitated.H2receptorexistsingastricwallcells,whenagitatedbyhistaminethesecretionofgastricacidisenhanced,causingpepticulcer.H2receptorantagonistcanspecificallybindwithH2receptorbutwithoutagitation.

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e.g.2angiotensin-convertingenzymeinhibitor(血管担心素转化酶抑制剂)forhypertensionangiotensinⅠisconvertedtoangiotensinⅡbyangiotensin-convertingenzyme.angiotensinⅡcanbindwithangiotensinreceptor(AT,existinginvascularsmoothmuscle),leadingtovasoconstrictionandriseofbloodpressure.angiotensin-convertingenzymeinhibitorsuchasCaptopril（卡托普利）canbindwiththeconvertingenzymes,thusangiotensinⅠcouldn'tbindtotheconvertingenzymesandwon’tbeconvertedtoangiotensinⅡ.新药研发医学知识培训第20页⑤ClinicalobservationofdrugactioninpracticeNewpharmacologicalactionwhichisnotdetectedinanimalmodelsmaybediscoveredinclinicalapplication.thiazidediuretics(噻嗪类利尿剂)areusedforthetreatmentofedema(水肿),theirantihypertensiveeffectswasnotpredictedfromanimalscreeningtest,butidentifiedafterthedrugsweremarketedandbeingusedinpractice.新药研发医学知识培训第21页6.2Pre-clinicalstudies

①medicinalchemistrystudies:technologyforproduction,chemicalandphysicalproperties,stability,dosageform,standardsforqualitycontrol

新药研发医学知识培训第22页②pharmacologicalandtoxicologicalstudiesinclude:pharmacodynamic（药品效应动力学）studies:drugaction(therapeuticeffectandadverseeffect)dose-effectrelationship(minimaleffectivedose,maximaleffect,medianeffectivedose,medianlethaldose)mechanismofaction（作用机制）:interactionwithitstargetpharmacokinetic（药品代谢动力学）studies:absorption,distribution,metabolismandexcretionofthedrugtoxicityinanimals：acutetoxicity,chronictoxicityspecialtoxicity新药研发医学知识培训第23页SomeimportantdefinitionsintoxicologicalassessmentAcutetoxicitytesting:acutetoxicreactionswithin24hoursaftersingledosingChronictoxicitytesting:toxicreactionswhichresultfromrepeateddoses,usuallyforthreemonthsLD50(medianlethaldose):thedosethatkills50%ofanimalsED50(medianeffectivedose):thedosecausingtherapeuticeffectsin50%ofexperimentalanimalstherapeuticindex=LD50/ED50

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新药研发医学知识培训第25页Significanceofpreclinicalstudydeterminethepossibilityofconductingclinicaltrialspredictpossibletoxicityandsafetyrangeinmanprovidereferenceforselectionofinitialdoseinclinicaltrials新药研发医学知识培训第26页6.3Clinicaltrails:PhaseⅠ:smallscalestudieson20-30volunteerstoprovethesafetyinmanaswellasthetolerability,thewholeprocesslast6to9months.dose-rangingstudy(剂量递增试验)：todetermineappropriatedosesfortherapeuticuseandtolerability(maximumtolerateddose最大耐受剂量)rmedconsent(知情同意书)：informationaboutaparticulartreatmentortestforsubjectstodecidewhetherornottoundergosuchtreatmentortest.

新药研发医学知识培训第27页PhaseⅡ:randomized,controlledandblindstudyareusedtodeterminethetherapeuticeffect,indicationandadversereactionofthenewtherapeuticagentonpatients,thetestsubjectsshouldbenolessthan100pairs.PhaseⅢ:largescalestudy(usuallyinmulti-centerstudyworldwide)tofurtherevaluateefficacyandsafetyofthenewdrug.thetestsubjectsshouldbenolessthan300.Afterphase3studies,anewdrugapplication(新药申请)issubmittedtotheregulatoryauthoritieswitharequestforproductlicense.

新药研发医学知识培训第28页PhaseⅣ:post-marketingstudyunderwideapplicationofthenewdrugtoexaminethetherapeuticeffectsandadversereactionsofthenewdrugaswellastodiscovernewindicationsandadversereactionsthatwerenotuncoveredbefore.Thetestsubjectsshouldbenolessthan.

新药研发医学知识培训第29页Withdrawalofcerivastatin(西立伐他汀)formthemarket:Cerivastatinisasyntheticmemberoftheclassofstatinsusedtolowercholesterolandpreventcardiovasculardisease.Itwasmarketedinthelate1990s.Duringpost-marketingsurveillance,52deathswerereportedinpatientsusingceriv