药物非房室模型分析PPT课件

.,1,NONCOMPARTMENTALANALYSIS,Deficienciesofcompartmentalanalysis:Lackofmeaningfulphysiologicalbasisforderivedparameters.Lackofrigorouscriteriatodetermine#ofcompartmentsnecessarytodescribedisposition.Lackofabilitytoelucidateorganspecificelimination.Inabilitytorelatederivedparameterstoquantifiablephysiologicalparameters.Inabilitytopredictimpactofpathophysiology.Inabilitytoprovideinsightintomechanismofdrug-druganddrug-nutrientinteractions.Highlysensitivetosamplingfrequency.,.,2,GENERALPRINCIPLESOFSTATISTICALMOMENTS,MOMENT:Amathematicaldescriptionofadiscretedistribution.,STATISTICALMOMENTS:UtilizedinchemicalengineeringtodescribeflowdataFirstappliedtobiologicalsystemsbyPerlandSamuelin1969todescribethekineticsofcholesterol,.,3,ExamplesofStatisticalMomentUsage,InstatisticsInphysics,M0,N,weight,M1,(mean),Centerofmass,M2,(variance),Momentofinertia,M3,(skewness),M4,(kurtosis),.,4,Instatistics,themeanisameasureofasamplemeanandisactuallyanestimateofthetruepopulationmean.Inpharmacokinetics,wecancalculatethemomentofthetheoreticalprobabilitydensityfunction(i.e.,thesolutionofadifferentialequationdescribingtheplasmaconcentrationtimedata),orwecancalculatemomentsfrommeasuredplasmaconcentration-timedata.Thesecurvesarereferredtoassamplemomentsandareestimatesofthetruecurves.,.,5,AssumeatheoreticalrelationshipofC(t)asafunctionoftime.Thenon-normalizedmoments,Sr,abouttheoriginarecalculatedas:,.,6,Non-normalizedmomentsKineticparameter,AUCAreaunderthecurve,AUMCAreaunderthemomentcurve,.,7,From:RowlandM,TozerTN.ClinicalPharmacokineticsConceptsandApplications,3rdedition,WilliamsandWilkins,1995,p.487.,.,8,NormalizedmomentsKineticparameter,Firstmoment:,MRTMeanresidencetime,.,9,AREADETERMINATION,A.IntegrationofSpecificFunction,MustelucidatethespecificfunctionInfluencedbythequalityofthefit,.,10,B.NumericalIntegration,LineartrapezoidalLogtrapezoidal,.,11,B.NumericalIntegration,Lineartrapezoidal,.,12,B.NumericalIntegration,Lineartrapezoidal,Advantages:Simple(cancalculatebyhand),Disadvantages:AssumesstraightlinebtwndatapointsIfcurveissteep,errormaybelargeUnderoroverestimatedependsonwhethercurveisascendingofdescending,.,13,.,14,B.NumericalIntegration,LineartrapezoidalLogtrapezoidal,.,15,B.NumericalIntegration,LineartrapezoidalLogtrapezoidal,Advantages:HandcalculatorVeryaccurateformono-exponentialVeryaccurateinlatetimepointswhereintervalbtwnpointsissubstantiallyincreased,Disadvantages:LimitedapplicationMayproducelargeerrorsonanascendingcurve,nearthepeak,orsteeplydecliningpolyexponentialcurve,.,16,B.NumericalIntegration,LineartrapezoidalLogtrapezoidalExtrapolationtoinfinity,Assumeslog-lineardecline,.,17,.,18,Time(hr)C(mg/L)02.5512.0031.1350.7070.43100.20180.025,AUCDetermination,Area(mg-hr/L)-2.2753.131.831.130.9450.900Total10.21,AUMCDetermination,Cxt(mg/L)(hr)02.003.393.503.012.000.45,Area(mg-hr2/L)-1.005.396.896.517.529.8037.11,.,19,.,20,CLEARANCECONCEPTS,ORGAN,Q,Ca,Q,Cv,elimination,IfCvCa,thenitisaclearingorgan,.,21,RateIn=QCa,RateOut=QCv,Rateofelimination=QCaQCv,=Q(CaCv),.,22,ExtractionRatio:Ratiooftherateofxenobioticeliminationandtherateatwhichxenobioticenterstheorgan.,.,23,Clearance:Thevolumeofbloodfromwhichallofthedrugwouldappeartoberemovedperunittime.,.,24,RelationshipbetweenCL&Q,SinceCL=QE,ifE1:CLQ,Perfusionrate-limitedclearance,.,25,TotalClearance,Total(systemic)Clearance:,.,26,TotalClearance,Total(systemic)Clearance:,.,27,Additivityofclearance,Rateofelimination=RateofRenalExcretion+RateofHepaticMetabolism,Dividingremovalratebyincomingconcentration:,TotalClearance=RenalClearance+HepaticClearance,CLT=CLR+CLH,.,28,Exception:sig.pulmonaryelimination,From:RowlandM,TozerTN.ClinicalPharmacokineticsConceptsandApplications,3rdedition,WilliamsandWilkins,1995,p.12.,.,29,100mgdrugadministeredtoavolunteerresultedin10mgexcretedinurineunchanged:,.,30,ApplicationofClearanceConcepts,Predictionoftheeffectofpathophysiologicalchanges,Anewantibiotichasjustbeenintroducedontothemarket.Currently,therearenostudiesexaminingtheeffectofrenaldiseaseonthepharmacokineticsofthiscompound.Isdosageadjustmentnecessaryforthisdrugwhenusedinptswithrenalfailure?Howcanwegainsomeinsightintothisquestion?Astudyinnormalvolunteerswasrecentlypublishedandthefollowingdatawasincluded(mean):,.,31,ApplicationofClearanceConcepts,Predictionoftheeffectofpathophysiologicalchanges,CLT=1.2L/hrDiv=500mgAmountinurineunchanged=63mg,.,32,Mechanismsofalteredelimination,Verapamilhasbeenshowntoelevateserumdigoxinconcentrationsinpatientsreceivingbothdrugsconcurrently.AstudybyPedersenetal(ClinPharmacolTher30:311-316,1981.)examinedthisinteractionwiththefollowingresults.:,TreatmentDigoxinDig+verapamil,CLT3.282.17,CLR2.181.73,CLNR1.100.44,.,33,STEADY-STATEVOLUMEOFDISTRIBUTION,Cf,Cbp,Cf,Cbt,VP,VT,.,34,Cf,Cbp,Cf,Cbt,VP,VT,CP=Cf+CbpCT=Cf+Cbt,.,35,Atsteady-state:,Substitute:,.,36,Simplifying:,.,37,Usingbloodconcentrations:,.,38,Calculationviamomentanalysis:,Assumptions:LineardispositionAdministeredandeliminatedviasamplingsiteInstantaneousinput,.,39,Ifadministrationviaashortterminfusion:,K0=infusionrateT=infusionduration,.,40,MEANRESIDENCE/TRANSITTIME,Administrationofasmalldosemayrepresentalargenumberofmolecules:,Dose=1mgMW=300daltons#ofmolecules=(10-3g/300)x(6.023x1023)2x1018molecules,.,41,Instantaneousadministrationoftheentiredosewillresultinxenobioticmoleculesspendingvariousamountsoftimeinthebody.Evaluationofthetimevariousmoleculesspendinthebody(residencetime)canbecharacterizedinthesamemannerasanystatisticaldistribution.,Meanresidencetime:Theaveragetimethemoleculesofagivendosespendinthebody.,.,42,Aconceptualunderstandingcanbegainedfromthefollowingexample:Assumeachildreceived20dimesforhisbirthdayandimmediatelyplacestheminhispiggybank.Overthenextmonth,heperiodicallyremoves1ormoredimesfromthepiggybanktopurchasecandy.Specifically,3daysafterplacingthecoinsinhisbankheremoves5dimes,onday10heremoves4dimes,onday21heremoves6dimesandonday30heremoves5dimes.Atthe30thdayafterplacingthecoinsinhisbank,allofthecoinshavebeenremoved.Hence,theeliminationofthedepositeddimesiscomplete.TheMRTofthedimesinthepiggybankissimplythesumofthetimesthatcoinsspendinthebankdivi