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1、PRINCIPLESOFCLINICALPHARMACOLOGYStevenP.Stratton,Ph.D.ResearchAssociateProfessorofMedicineUniversityofArizonaAddress:ArizonaCancerCenter1515NCampbellAvePOBox245024Tucson,AZ85724(520)626-9295RunningTitle:ClinicalPharmacology10LearningObjectives1.DefinePharmac
2、okinetics&Pharmacodynamics2.Identifypharmacokinetic/pharmacodynamicapproaches,terminology,andparameters3.Recognizeanddevelopendpointsforpharmacokinetic/pharmacodynamicmodeling4.Identifybarrierstomolecularlytargeteddrugdevelopment5.Understandpracticalconsider
3、ationsindesignofpharmacokineticstudiesinclinicalprotocolsIntroductiontoPharmacokineticsandPharmacodynamicsAntineoplasticchemotherapeuticagentshavethelowesttherapeuticindicesofcommonlyusedclassesofdrugs1.Thedistinctionbetweendrugandpoisonisverysmall.Thus,phar
4、macologicallyrationalapproachesarecrucialtoavoidingdisastrousoutcomes.Adrugisanypurechemicalsubstancethataltersanormalphysiologicprocesswhenadministeredtoanorganism.Tostudyhowdrugswork,pharmacologistshavemystifiedtheprocessbycreatingcomplextermstodescriberel
5、ativelysimpleconcepts.Thesetermsincludepharmacokineticsandpharmacodynamics.Therearefourpossibleoutcomesfollowingdrugadministration.Theseoutcomesinclude:·Efficacywithouttoxicity·Efficacywithtoxicity·Toxicitywithoutefficacy·NeithertoxicitynorefficacyPharmacoki
6、neticandpharmacodynamicmodelingincorporatedintoclinicaltrialdesigncanbeusedtooptimizethebestoutcomefordrugtherapy2.10Pharmacokinetics(PK)isthemathematicalstudyofdrugdisposition(absorption,distribution,metabolism,andexcretion).Intriteterms,PKstudieswhatthebod
7、ydoestothedrug.Pharmacodynamics(PD)isthestudyofthedose-responserelationship(thecoreprincipleofpharmacology),whichisoftenrepresentedasaSigmoidEmaxModeldescribedbytheModifiedHillEquation:E=(EmaxxPKH)÷(PK50H+PKH)whereE=effect,Emax=maximaleffect,PK=chosenPKparam
8、eter,PK50=parametervalueat50%ofmaximaleffect,andH=Hill’sconstant.Againintriteterms,PDstudieswhatthedrugdoestothebody.Thegreatestriskreductionindrugdevelopmentinthepast10-15yearsisduetotheincorpo
