新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)專家講座

UnitoneTxtADevelopmentofnewdrugs新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第1頁Newwordsandexpressionacute:acuteinfection（急性感染）,acuteleukemia（急性白血病）chronic:chronicgastritis（慢性胃炎）agonist:stimulatorantagonist:blockeradversereaction（不良反應(yīng)）:anybadeffectorundesirableeffectcausedbydruguseatnormaldose（正常劑量）新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第2頁newchemicalentity(新化學(xué)實(shí)體):newcompoundshowspharmacologicalactivityagainstcertaindisease,whichisalsocalledleadcompound(先導(dǎo)化合物)ordrugcandidate(候選藥品)in-vitro（體外）:outsideoforganismsinvivo（體內(nèi)）:withinawholelivingorganism新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第3頁1.Whatisanewdrug?Chemicalstructure（化學(xué)成份）

Dosageform(劑型）Routeofadministration（給藥路徑）Indication（適應(yīng)癥）Newdrug新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第4頁2.Whydoweneednewdrugs?manyincurablediseasesstillawaitconquesttoproducenewdrugsthataresuperiorthanexistingmedicationstheultimategoal:toprovideeffective,accessibleandaffordablemedicinesforall新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第5頁①Inthepast,drugswereextractedfromplantandanimalsources,butthepurityofdrugswasverylimited.quinine（奎寧）:extractedfromthebarkofcinchona（金雞納樹皮）,itsantimalarial（抗瘧疾）functionwasdiscoveredbytheIndiansinNorthAmerica

3.Evolutionofnewdrug新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第6頁②From1900chemicallysynthesizeddrugsbecameavailable,thepurityofdrugswereremarkablypromotedwhichincreasedthespecificityofaction.e.g.quininecanbeartificiallysynthesizedin1945Nowadaysmostwesternmedicinesaretotallysynthesizedorsemi-synthesized新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第7頁③Withthedevelopmentofgeneticengineering（基因工程）moredrugswillbeproducedartificially.

e.g.thefirstgeneticallyengineereddrugisrh-insulin(forthetreatmentofdiabetes)andwasfirstmarketedinAmericain1982.新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第8頁4.RegulationofdrugdevelopmentTherangeofnovelchemicalentitiesdevelopedhasoccasionallyledtounexpectedtoxicity.Inordertoensurethesafetyandefficacyofnewdrugs,theirdevelopmentmustfollowstatutoryprocedures（法定程序）.新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第9頁

Thalidomide--------abigtragedy!

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

新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第10頁

Developinganewdrugisahighlycomplex,time-consuming,riskyandcostlyprocess.5.Anoverviewofnewdrugdevelopment新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第11頁complexandtime-consumingNewdrugdevelopmentrequiresmultidisciplinaryeffortsformanyyears,involvingnumerousstepsandmanysophisticatedtechniques0.5-1year3-4years6-8years2-3years新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第12頁risky:

OnlyaverysmallportionofNCEscanbefinallymarketedasdrugproduct新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第13頁costly:

Onebillion新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第14頁6.Developmentofnewdrugs6.1Strategiesfordiscoveringnewchemicalentities①Serendipity:Thenewtherapeuticagentisdiscoveredbychance.e.g.thediscoveryofpenicillin

AlexanderFleming

penicillum新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第15頁②Molecularroulette（分子輪盤賭）Agreatmanyofnewchemicalstructuresweresynthesizedrandomlyandscreenedbyanimalorin-vitromodelsofhumandiseasetoseeifanyofthenewlyobtainedstructuresprovecertaineffect.Disadvantage:wasteful,dependentonsensitivemodelsforscreening新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第16頁③Minorstructurechangesinexistingagents

Penicillin，青霉素Penicillin∨Oxacillin，苯唑西林Ampicillin，氨芐西林新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第17頁Disadvantagesofpenicillin:unstabletoacidunstabletoβ-lactamase(內(nèi)酰胺酶)littleeffectonGramnegativebacteria（革蘭氏陰性菌）新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第18頁

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

新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第19頁

e.g.2angiotensin-convertingenzymeinhibitor(血管擔(dān)心素轉(zhuǎn)化酶抑制劑)forhypertensionangiotensinⅠisconvertedtoangiotensinⅡbyangiotensin-convertingenzyme.angiotensinⅡcanbindwithangiotensinreceptor(AT,existinginvascularsmoothmuscle),leadingtovasoconstrictionandriseofbloodpressure.angiotensin-convertingenzymeinhibitorsuchasCaptopril（卡托普利）canbindwiththeconvertingenzymes,thusangiotensinⅠcouldn'tbindtotheconvertingenzymesandwon’tbeconvertedtoangiotensinⅡ.新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第20頁⑤ClinicalobservationofdrugactioninpracticeNewpharmacologicalactionwhichisnotdetectedinanimalmodelsmaybediscoveredinclinicalapplication.thiazidediuretics(噻嗪類利尿劑)areusedforthetreatmentofedema(水腫),theirantihypertensiveeffectswasnotpredictedfromanimalscreeningtest,butidentifiedafterthedrugsweremarketedandbeingusedinpractice.新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第21頁6.2Pre-clinicalstudies

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

新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第22頁②pharmacologicalandtoxicologicalstudiesinclude:pharmacodynamic（藥品效應(yīng)動(dòng)力學(xué)）studies:drugaction(therapeuticeffectandadverseeffect)dose-effectrelationship(minimaleffectivedose,maximaleffect,medianeffectivedose,medianlethaldose)mechanismofaction（作用機(jī)制）:interactionwithitstargetpharmacokinetic（藥品代謝動(dòng)力學(xué)）studies:absorption,distribution,metabolismandexcretionofthedrugtoxicityinanimals：acutetoxicity,chronictoxicityspecialtoxicity新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第23頁SomeimportantdefinitionsintoxicologicalassessmentAcutetoxicitytesting:acutetoxicreactionswithin24hoursaftersingledosingChronictoxicitytesting:toxicreactionswhichresultfromrepeateddoses,usuallyforthreemonthsLD50(medianlethaldose):thedosethatkills50%ofanimalsED50(medianeffectivedose):thedosecausingtherapeuticeffectsin50%ofexperimentalanimalstherapeuticindex=LD50/ED50

新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第24頁

新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第25頁Significanceofpreclinicalstudydeterminethepossibilityofconductingclinicaltrialspredictpossibletoxicityandsafetyrangeinmanprovidereferenceforselectionofinitialdoseinclinicaltrials新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第26頁6.3Clinicaltrails:PhaseⅠ:smallscalestudieson20-30volunteerstoprovethesafetyinmanaswellasthetolerability,thewholeprocesslast6to9months.dose-rangingstudy(劑量遞增試驗(yàn))：todetermineappropriatedosesfortherapeuticuseandtolerability(maximumtolerateddose最大耐受劑量)rmedconsent(知情同意書)：informationaboutaparticulartreatmentortestforsubjectstodecidewhetherornottoundergosuchtreatmentortest.

新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第27頁P(yáng)haseⅡ:randomized,controlledandblindstudyareusedtodeterminethetherapeuticeffect,indicationandadversereactionofthenewtherapeuticagentonpatients,thetestsubjectsshouldbenolessthan100pairs.PhaseⅢ:largescalestudy(usuallyinmulti-centerstudyworldwide)tofurtherevaluateefficacyandsafetyofthenewdrug.thetestsubjectsshouldbenolessthan300.Afterphase3studies,anewdrugapplication(新藥申請)issubmittedtotheregulatoryauthoritieswitharequestforproductlicense.

新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第28頁P(yáng)haseⅣ:post-marketingstudyunderwideapplicationofthenewdrugtoexaminethetherapeuticeffectsandadversereactionsofthenewdrugaswellastodiscovernewindicationsandadversereactionsthatwerenotuncoveredbefore.Thetestsubjectsshouldbenolessthan.

新藥研發(fā)醫(yī)學(xué)知識培訓(xùn)第29頁Withdrawalofcerivastatin(西立伐他汀)formthemarket:Cerivastatinisasyntheticmemberoftheclassofstatinsusedtolowercholesterolandpreventcardiovasculardisease.Itwasmarketedinthelate1990s.Duringpost-marketingsurveillance,52deathswerereportedinpatientsusingceriv