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AppliedBiopharmaceutics&Pharmacokinetics>Chapter5.IntravenousInfusion>

INTRAVENOUSINFUSION:INTRODUCTION
Drugsmaybeadministeredtopatientsbyoneofseveralroutes,includingoral,topical,orparenteralroutesof
administration.Examplesofparenteralroutesofadministrationincludeintravenous,subcutaneous,and
intramuscular.Intravenous(IV)drugsolutionsmaybegiveneitherasabolusdose(injectedallatonce)or
infusedslowlythroughaveinintotheplasmaataconstantorzeroorderrate.Themainadvantageforgivinga
drugbyIVinfusionisthatIVinfusionallowsprecisecontrolofplasmadrugconcentrationstofittheindividual
needsofthepatient.Fordrugswithanarrowtherapeuticwindow(eg,heparin),IVinfusionmaintainsan
effectiveconstantplasmadrugconcentrationbyeliminatingwidefluctuationsbetweenthepeak(maximum)and
trough(minimum)plasmadrugconcentration.Moreover,theIVinfusionofdrugs,suchasantibiotics,maybe
givenwithIVfluidsthatincludeelectrolytesandnutrients.Furthermore,thedurationofdrugtherapymaybe
maintainedorterminatedasneededusingIVinfusion.
TheplasmadrugconcentrationversustimecurveofadruggivenbyconstantIVinfusionisshowninFigure51.
Becausenodrugwaspresentinthebodyatzerotime,druglevelrisesfromzerodrugconcentrationand
graduallybecomesconstantwhenaplateauorsteadystatedrugconcentrationisreached.Atsteadystate,the
rateofdrugleavingthebodyisequaltotherateofdrug(infusionrate)enteringthebody.Therefore,atsteady
state,therateofchangeintheplasmadrugconcentration,dC p/dt=0,and

Figure51.

PlasmaleveltimecurveforconstantIVinfusion.

Basedonthissimplemassbalancerelationship,apharmacokineticequationforinfusionmaybederived

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dependingonwhetherthedrugfollowsoneortwocompartmentkinetics.

ONECOMPARTMENTMODELDRUGS
ThepharmacokineticsofadruggivenbyconstantIVinfusionfollowsazeroorderinputprocessinwhichthe
drugisinfuseddirectlyintothesystemicbloodcirculation.Equation5.2,below,givestheplasmadrug
concentrationatanytimeduringtheIVinfusion,wheretisthetimeforinfusion.ThegraphofEquation5.2
appearsinFigures51and52.Formostdrugs,eliminationofdrugfromtheplasmaisafirstorderprocess.
Therefore,inthisonecompartmentmodel,theinfuseddrugfollowszeroorderinputandfirstorderoutput.The
changeintheamountofdruginthebodyatanytime(dDB/dt)duringtheinfusionistherateofinputminusthe
rateofoutput.

Figure52.

PlasmadrugconcentrationsversustimeprofilesafterIVinfusion.IVinfusionisstoppedatsteadystate(A)orpriorto
steadystate(B).Inbothcases,plasmadrugconcentrationsdeclineexponentially(firstorder)accordingtoasimilar
slope.

whereDB istheamountofdruginthebody,Ristheinfusionrate(zeroorder),andkistheeliminationrate
constant(firstorder).
IntegrationofEquation5.1andsubstitutionofDB =CpVD gives

Asthedrugisinfused,thevaluefortime(t)increasesinEquation5.2.Atinfinitetime,t=,ekt approaches
zero,andEquation5.2reducestoEquation5.4.

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SteadyStateDrugConcentration(CSS)andTimeNeededtoReachCSS
Asstatedearlier,therateofdrugleavingthebodyisequaltotherateofdrugenteringthebody(infusionrate)
atsteadystate(Fig.52).Inotherwords,thereisnonetchangeintheamountofdruginthebody,DB,asa
functionoftimeduringsteadystate.Drugeliminationoccursaccordingtofirstordereliminationrate.Whenever
theinfusionstopseitheratsteadystateorbeforesteadystateisreached,thelogdrugconcentrationdeclines
accordingtofirstorderkineticswiththeslopeoftheeliminationcurveequaltok/2.3.Iftheinfusionisstopped
beforesteadystateisreached,theslopeoftheeliminationcurveremainsthesame(Fig.52B).
Mathematically,thetimetoreachtruesteadystatedrugconcentration,CSS,wouldtakeaninfinitetime.The
timerequiredtoreachthesteadystatedrugconcentrationintheplasmaisdependentontheeliminationrate
constantofthedrugforaconstantvolumeofdistribution,asshowninEquation5.4.Becausedrugeliminationis
exponential(firstorder),theplasmadrugconcentrationbecomesasymptotictothetheoreticalsteadystate
plasmadrugconcentration.Forazeroordereliminationprocess,iftherateofinputisgreaterthantherateof
elimination,plasmadrugconcentrationwillkeepincreasingandnosteadystatewillbereached.Thisisa
potentiallydangeroussituationthatwilloccurwhensaturationofmetabolicprocessoccurs.
Inclinicalpractice,aplasmadrugconcentrationpriorto,butasymptoticallyapproaching,thetheoreticalsteady
stateisconsideredthesteadystateplasmadrugconcentration(C SS).InaconstantIVinfusion,drugsolutionis
infusedataconstantorzeroorderrate,R.DuringtheIVinfusion,thedrugconcentrationincreasesinthe
plasmaandtherateofdrugeliminationincreasesbecauserateofeliminationisconcentrationdependent(ie,
rateofdrugelimination=kC p).C p keepsincreasinguntilsteadystateisreached,atwhichtimetherateof
druginput(IVinfusionrate)equalstherateofdrugoutput(eliminationrate).Theresultingplasmadrug
concentrationatsteadystate(CSS)isrelatedtotherateofinfusionandinverselyrelatedtothebodyclearance
ofthedrug,asshowninEquation5.5.
Inclinicalpractice,theactivityofthedrugwillbeobservedwhenthedrugconcentrationisclosetothedesired
plasmadrugconcentration,whichisusuallythetargetordesiredsteadystatedrugconcentration.Thetimeto
reach90%,95%,and99%ofthesteadystatedrugconcentration,C SS,maybecalculated(Table5.1).For
therapeuticpurposes,thetimefortheplasmadrugconcentrationtoreachmorethan95%ofthesteadystate
drugconcentrationintheplasmaisoftenestimated.AsdetailedinTable5.1,afterIVinfusionofthedrugfor5
halflives,theplasmadrugconcentrationwillbebetween95%(4.32t1/2)and99%(6.65t1/2)ofthesteady
statedrugconcentration.Thus,thetimeforadrugwhoset1/2 is6hourstoreachatleast95%ofthesteady
stateplasmadrugconcentrationwillbe5t1/2,or5 x 6hours=30hours.ThecalculationofthevaluesinTable
5.1isgivenintheexamplethatfollows.

Table5.1Numberoft1/2 toReachaFractionofCSS
PercentofCSS Reacheda

NumberofHalfLives

90

3.32

95

4.32

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99

6.65

Css isthesteadystatedrugconcentrationinplasma.
Anincreaseintheinfusionratewillnotshortenthetimetoreachthesteadystatedrugconcentration.Ifthe
drugisgivenatamorerapidinfusionrate,ahighersteadystatedruglevelwillbeobtained,butthetimeto
reachsteadystateisthesame(Fig.53).Thisequationmayalsobeobtainedwiththefollowingapproach.At
steadystate,therateofinfusionequalstherateofelimination.Therefore,therateofchangeintheplasmadrug
concentrationisequaltozero.

Figure53.

PlasmaleveltimecurveforIVinfusionsgivenatratesofRand2R,respectively.

Equation5.6showsthatthesteadystateconcentration(C SS)isdependentonthevolumeofdistribution,the
eliminationrateconstant,andtheinfusionrate.Alteringanyoneofthesefactorscanaffectsteadystate
concentration.

Examples
1.Anantibiotichasavolumeofdistributionof10Landakof0.2hr1.Asteadystateplasmaconcentrationof
10 g/mLisdesired.Theinfusionrateneededtomaintainthisconcentrationcanbedeterminedasfollows.
Equation5.6canberewrittenas

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Assumethepatienthasauremicconditionandtheeliminationrateconstanthasdecreasedto0.1hr1.To
maintainthesteadystateconcentrationof10 g/mL,wemustdetermineanewrateofinfusionasfollows.

Whentheeliminationrateconstantdecreases,theinfusionratemustdecreaseproportionatelytomaintainthe
sameCSS.However,becausetheeliminationrateconstantissmaller(ie,theeliminationt1/2 islonger),the
timetoreachCSS willbelonger.
2.Aninfinitelylongperiodoftimeisneededtoreachsteadystatedruglevels.However,inpracticeitisquite
acceptabletoreach99%CSS (ie,99%steadystatelevel).UsingEquation5.6,weknowthatthesteadystate
levelis

and99%steadystatelevelis

SubstitutingintoEquation5.2forC p,wecanfindthetimeneededtoreachsteadystatebysolvingfort.

Takethenaturallogarithmonbothsides:

substituting(0.693/t1/2)fork,

Noticethatintheequationdirectlyabove,thetimeneededtoreachsteadystateisnotdependentontherateof
infusion,butonlyontheeliminationhalflife.Usingsimilarcalculations,thetimeneededtoreachany
percentageofthesteadystatedrugconcentrationmaybeobtained(Table5.1).

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Intravenousinfusionmaybeusedtodeterminetotalbodyclearanceiftheinfusionrateandsteadystatelevel
areknown,aswithEquation5.6repeatedhere:

becausetotalbodyclearance,ClT,isequaltoVDk,

3.Apatientwasgivenanantibiotic(t1/2 =6hr)byconstantIVinfusionatarateof2mg/hr.Attheendof2
days,theserumdrugconcentrationwas10mg/L.CalculatethetotalbodyclearanceClT forthisantibiotic.
ThetotalbodyclearancemaybeestimatedfromEquation5.7.Theserumsamplewastakenafter2daysor48
hoursofinfusion,whichtimerepresents8 x t1/2,therefore,thisserumdrugconcentrationapproximatestheC
.

SS

INFUSIONMETHODFORCALCULATINGPATIENTELIMINATIONHALF
LIFE
TheCpversustimerelationshipthatoccursduringanIVinfusion(Eq.5.2)maybeusedtocalculatek,or
indirectlytheeliminationhalflifeofthedruginapatient.Someinformationabouttheeliminationhalflifeofthe
druginthepopulationmustbeknown,andoneortwoplasmasamplesmustbetakenataknowntimeafter
infusion.Knowingthehalflifeinthegeneralpopulationhelpstodetermineifthesampleistakenatsteadystate
inthepatient.Tosimplifycalculation,Equation5.2isarrangedtosolvefork:

Since

SubstitutingintoEquation5.2

Rearrangingandtakingthelogonbothsides,

whereCp istheplasmadrugconcentrationtakenattimetC SS istheapproximatesteadystateplasmadrug

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concentrationinthepatient.

Example1
Anantibiotichasaneliminationhalflifeof36hoursinthegeneralpopulation.ApatientwasgivenanIV
infusionofanantibioticataninfusionrateof15mg/hr.Bloodsamplesweretakenat8andat24hoursand
plasmadrugconcentrationswere5.5and6.5mg/L,respectively.Estimatetheeliminationhalflifeofthedrugin
thispatient.
Solution
Becausethesecondplasmasamplewastakenat24hours,or24/6=4halflivesafterinfusion,theplasmadrug
concentrationinthissampleisapproaching95%ofthetrueplasmasteadystatedrugconcentrationassuming
theextremecaseoft1/2 =6hours.
BysubstitutionintoEquation5.8,

Theeliminationhalflifecalculatedinthismannerisnotasaccurateasthecalculationoft1/2 usingmultiple
plasmadrugconcentrationtimepointsafterasingleIVbolusdoseorafterstoppingtheIVinfusion.However,
thismethodmaybesufficientinclinicalpractice.Asthesecondbloodsampleistakenclosertothetimefor
steadystate,theaccuracyofthismethodimproves.Atthe30thhour,forexample,theplasmaconcentration
wouldbe99%ofthetruesteadystatevalue(correspondingto30/6or5eliminationhalflives),andlesserror
wouldresultinapplyingEquation5.8.
WhenEquation5.8wasusedasintheexampleabovetocalculatethedrugt1/2 ofthepatient,thesecond
plasmadrugconcentrationwasassumedtobethetheoreticalCSS.Asdemonstratedbelow,whent1/2 andthe
correspondingvaluesaresubstituted,

(NotethatC SS isinfactthesameastheconcentrationat24hoursintheexampleabove.)
Inpractice,beforestartinganIVinfusion,anappropriateinfusionrate(R)isgenerallycalculatedfromEquation
5.8usingliteraturevaluesforCSS,k,andVD orClT.Twoplasmasamplesaretakenandthesamplingtimes
recorded.Thesecondsampleshouldbetakennearthetheoreticaltimeforsteadystate.Equation5.8would
thenbeusedtocalculateat1/2.Iftheeliminationhalflifecalculatedconfirmsthatthesecondsamplewas
takenatsteadystate,theplasmaconcentrationissimplyassumedasthesteadystateconcentrationandanew

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infusionratemaybecalculated.

Example2
Ifthedesiredtherapeuticplasmaconcentrationis8mg/Lfortheabovepatient(Example1),whatisasuitable
infusionrateforthepatient?
Solution
FromExample1,thetrialinfusionratewas15mg/hr.Assumingthesecondbloodsampleisthesteadystate
level,6.5mg/mL,theclearanceofthepatientis

Thenewinfusionrateshouldbe

Inthisexample,thet1/2 ofthispatientisalittleshorter,about3hours,comparedto36hoursreportedfor
thegeneralpopulation.Therefore,theinfusionrateshouldbealittlegreaterinordertomaintainthedesired
steadystatelevelof15mg/L.
Equation5.7orthesteadystateclearancemethodhasbeenappliedtotheclinicalinfusionofdrugs.Themethod
wasregardedassimpleandaccuratecomparedwithothermethods,includingthetwopointmethod(Hurleyand
McNeil,1988).

LOADINGDOSEPLUSIVINFUSION:ONECOMPARTMENTMODEL
Theloadingdose,DL,orinitialbolusdoseofadrug,isusedtoobtaindesiredconcentrationsasrapidlyas
possible.TheconcentrationofdruginthebodyforaonecompartmentmodelafteranIVbolusdoseisdescribed
by

andconcentrationbyinfusionattherateRis

AssumethatanIVbolusdoseDL ofthedrugisgivenandthatanIVinfusionisstartedatthesametime.The
totalconcentrationC p atthoursafterthestartofinfusionisC 1 +C2,duetothesumcontributionsofbolus
andinfusion,or

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Lettheloadingdose(DL)equaltheamountofdruginthebodyatsteadystate:

FromEquation5.4,CSSVD =R/k.Therefore,

SubstitutingDL =R/kinEquation5.11makestheexpressioninparenthesesinEquation5.11cancelout.
Equation5.11reducestoEquation5.13,whichisthesameexpressionforCSS orsteadystateplasma
concentration:

Therefore,ifanIVloadingdoseofR/kisgiven,followedbyanIVinfusion,steadystateplasmadrug
concentrationsareobtainedimmediatelyandmaintained(Fig.54).Inthissituation,steadystateisalso
achievedinaonecompartmentmodel,sinceratein=rateout(R=dDB/dt).

Figure54.

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IVInfusionwithloadingdoseDL.TheloadingdoseisgivenbyIVbolusinjectionatthestartoftheinfusion.Plasma
drugconcentrationsdeclineexponentiallyafterDL whereastheyincreaseexponentiallyduringtheinfusion.The
resultingplasmadrugconcentrationversustimecurveisastraightlineduetothesummationofthetwocurves.

Theloadingdoseneededtogetimmediatesteadystatedruglevelscanalsobefoundbythefollowingapproach.
Loadingdoseequation:

Infusionequation:

AddingupthetwoequationsyieldsEquation5.15,anequationdescribingsimultaneousinfusionafteraloading
dose:

Bydifferentiatingthisequationatsteadystate,weobtain

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Inordertomaintaininstantsteadystatelevel[(dC p/dt)=0],theloadingdoseshouldbeequaltoR/k.
Foraonecompartmentdrug,iftheDL andinfusionratearecalculatedsuchthatC 0 andCSS arethesameand
bothDL andinfusionarestartedconcurrently,thensteadystateandCSS willbeachievedimmediatelyafterthe
loadingdoseisadministered(Fig.54).Similarly,inFigure55,curvebshowsthebloodlevelafterasingle
loadingdoseofR/kplusinfusionfromwhichtheconcentrationdesiredatsteadystateisobtained.IftheDL is
notequaltoR/k,thensteadystatewillnotoccurimmediately.IftheloadingdosegivenislargerthanR/k,the
plasmadrugconcentrationtakeslongertodeclinetotheconcentrationdesiredatsteadystate(curvea).Ifthe
loadingdoseislowerthanR/k,theplasmadrugconcentrationswillincreaseslowlytodesireddruglevels(curve
c),butmorequicklythanwithoutanyloadingdose.

Figure55.

Intravenousinfusionwithloadingdosesa,b,andc.CurvedrepresentsanIVinfusionwithoutaloadingdose.

AnothermethodforthecalculationofloadingdoseDL isbasedonknowledgeofthedesiredsteadystatedrug
concentrationCSS andtheapparentvolumeofdistributionVD forthedrug,asshowninEquation5.18.

Formanydrugs,thedesiredC SS isreportedintheliteratureastheeffectivetherapeuticdrugconcentration.
TheVD andtheeliminationhalflifearealsoavailableforthesedrugs.

PracticeProblems
1.Aphysicianwantstoadministerananestheticagentatarateof2mg/hrbyIVinfusion.Theeliminationrate

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constantis0.1hr1,andthevolumeofdistribution(onecompartment)is10L.Whatloadingdoseshouldbe
recommendedifthedoctorwantsthedrugleveltoreach2 g/mLimmediately?
Solution

ToreachC SS instantly,

2.Whatistheconcentrationofadrug6hoursafteradministrationofaloadingdoseof10mgandsimultaneous
infusionat2mg/hr(thedrughasat1/2 of3hrandavolumeofdistributionof10L)?
Solution

3.Calculatethedrugconcentrationinthebloodafterinfusionhasbeenstopped.
Solution
Thisconcentrationcanbecalculatedintwoparts(seeFig.52,pointA).First,calculatetheconcentrationof
drugduringinfusionandsecond,calculatethefinalinfusionconcentration,C0.ThenusetheIVbolusdose
equation(C=C0ekt )forcalculationsforanyfurtherpointintime.Forconvenience,thetwoequationscanbe
combinedasfollows.

whereb=lengthoftimeofinfusionperiod,t=totaltime(infusionandpostinfusion),andtb=lengthoftime
afterinfusionhasstopped.
4.Apatientwasinfusedfor6hourswithadrug(k=0.01hr1VD =10L)atarateof2mg/hr.Whatisthe
concentrationofthedruginthebody2hoursaftercessationoftheinfusion?
Solution
UsingEquation5.19,

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Alternatively,wheninfusionstops,C'p iscalculated:

Thetwoapproachesshouldgivethesameanswer.
5.Anadultmaleasthmaticpatient(78kg,48yearsold)withahistoryofheavysmokingwasgivenanIV
infusionofaminophyllineatarateof0.5mg/kgperhr.Aloadingdoseof6mg/kgwasgivenbyIVbolus
injectionjustpriortothestartoftheinfusion.At2hoursafterthestartoftheIVinfusion,theplasma
theophyllineconcentrationwasmeasuredandfoundtocontain5.8 g/mLoftheophylline.TheapparentVD for
theophyllineis0.45L/kg.Aminophyllineistheethylenediaminesaltoftheophyllineandcontains80%of
theophyllinebase.
Becausethepatientwasrespondingpoorlytotheaminophyllinetherapy,thephysicianwantedtoincreasethe
plasmatheophyllineconcentrationinthepatientto10 g/mL.Whatdosagerecommendationwouldyougivethe
physician?Wouldyourecommendanotherloadingdose?
Solution
IfnoloadingdoseisgivenandtheIVinfusionrateisincreased,thetimetoreachsteadystateplasmadrug
concentrationswillbeabout4to5t1/2 toreach95%ofCSS.Therefore,asecondloadingdoseshouldbe
recommendedtorapidlyincreasetheplasmatheophyllineconcentrationto10 g/mL.Theinfusionratemust
alsobeincreasedtomaintainthisdesiredCSS.
ThecalculationofloadingdoseDL mustconsiderthepresentplasmatheophyllineconcentration.

whereSisthesaltformofthedrugandFisthefractionofdrugbioavailable.Foraminophylline,Sisequalto
0.80,andforanIVbolusinjection,Fisequalto1.

ThemaintenanceIVinfusionratemaybecalculatedafterestimationofthepatient'sclearance,ClT.Becausea

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loadingdoseandanIVinfusionof0.5mg/hrperkilogramwasgiventothepatient,theplasmatheophylline
concentrationof5.8mg/LisatsteadystateCSS.Totalclearancemaybeestimatedby

TheusualClT foradult,nonsmokingpatientswithuncomplicatedasthmaisapproximately0.65mL/minper
kilogram.HeavysmokingisknowntoincreaseCl T fortheophylline.
ThenewIVinfusionrate,R',iscalculatedby

6.Anadultmalepatient(43yearsold,80kg)istobegivenanantibioticbyIVinfusion.Accordingtothe
literature,theantibiotichasaneliminationt1/2 of2hours,aVDof1.25L/kg,andiseffectiveataplasmadrug
concentrationof14mg/L.Thedrugissuppliedin5mLampulscontaining150mg/mL.
a.Recommendastartinginfusionrateinmilligramsperhourandlitersperhour.
Solution
AssumetheeffectiveplasmadrugconcentrationisthetargetdrugconcentrationorCSS.

Becausethedrugissuppliedataconcentrationof150mg/mL,

Thus,R=3.23mL/hr.
b.Bloodsamplesweretakenfromthepatientat12,16,and24hoursafterthestartoftheinfusion.Plasma
drugconcentrationswereasshownbelow:
t(hr) Cp (mg/L)

12

16.1

16

16.3

24

16.5

Fromthisadditionaldata,calculatethetotalbodyclearanceClT forthedruginthispatient.
Solution
Becausetheplasmadrugconcentrationsat12,16,and24hoursweresimilar,steadystatehasessentially
beenreached.(Note:Thecontinuousincreaseinplasmadrugconcentrationscouldbecausedbydrug
accumulationduetoasecondtissuecompartment,orcouldbeduetovariationinthedrugassay.)Assuming
aCSS of16.3mg/mL,ClT iscalculated.

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c.Fromtheabovedata,estimatetheeliminationhalflifefortheantibioticinthispatient.
Solution
Generally,theapparentvolumeofdistribution(VD)islessvariablethant1/2.Assumingthattheliterature
valueforVD is1.25L/kg,thent1/2 maybeestimatedfromtheClT.

Thusthet1/2 fortheantibioticinthispatientis2.32hours,whichisingoodagreementwiththeliterature
valueof2hours.
d.Afterreviewingpharmacokineticsoftheantibioticinthispatient,shouldtheinfusionratefortheantibiotic
bechanged?
Solution
Todecidewhethertheinfusionrateshouldbechanged,theclinicalpharmacistmustconsiderthe
pharmacodynamicsandtoxicityofthedrug.Assumingthedrughasawidetherapeuticwindowandshowsno
signofadversedrugtoxicity,theinfusionrateof485.1mg/hr,calculatedaccordingtopharmacokinetic
literaturevaluesforthedrug,appearstobecorrect.

ESTIMATIONOFDRUGCLEARANCEANDVD FROMINFUSIONDATA
Theplasmaconcentrationofadrugduringconstantinfusionwasdescribedintermsofvolumeofdistribution
andeliminationconstantkinEquation5.2.Alternatively,theequationmaybedescribedintermsofclearance
bysubstitutingforkintoEquation5.2withk=Cl/VD:

ThedrugconcentrationinthisphysiologicmodelisdescribedintermsofvolumeofdistributionofVD andtotal
bodyclearance(Cl).Theindependentparametersareclearanceandvolumeofdistributionkisviewedasa
dependentvariablethatdependsonClandVD.Inthismodel,thetimetoreachsteadystateandtheresulting
steadystateconcentrationwillbedependentonbothclearanceandvolumeofdistribution.Whenaconstant
volumeofdistributionisevident,thetimetoreachsteadystateistheninverselyrelatedtoclearance.Thus,
drugswithsmallclearancewilltakealongtimetoreachsteadystate.Althoughthisnewerapproachispreferred
bysomeclinicalpharmacists,thealternativeapproachtoparameterestimationwasknownforsometimein
classicalpharmacokinetics.Equation5.21hasbeenappliedinpopulationpharmacokineticstoestimatebothCl
andVD inindividualpatientswithoneormoredatapoints.However,clearanceinpatientsmaydiffergreatly
fromsubjectsinthepopulation,especiallysubjectswithdifferentrenalfunctions.Unfortunately,theplasma
samplestakenattimeequivalenttolessthanonehalflifeafterinfusionwasstartedmaynotbevery

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discriminating,duetothesmallchangeinthedrugconcentration.Bloodsamplestakenat34halfliveslater
aremuchmorereflectiveofthedifferenceinclearance.

INTRAVENOUSINFUSIONOFTWOCOMPARTMENTMODELDRUGS
ManydrugsgivenbyIVinfusionfollowtwocompartmentkinetics.Forexample,therespectivedistributionsof
theophyllineandlidocaineinhumansaredescribedbythetwocompartmentopenmodel.Withtwo
compartmentmodeldrugs,IVinfusionrequiresadistributionandequilibrationofthedrugbeforeastableblood
levelisreached.DuringaconstantIVinfusion,druginthetissuecompartmentisindistributionequilibriumwith
theplasmathus,constantCSS levelsalsoresultinconstantdrugconcentrationsinthetissueie,nonet
changeintheamountofdruginthetissueoccursatsteadystate.Althoughsomecliniciansassumethattissue
andplasmaconcentrationsareequalwhenfullyequilibrated,kineticmodelspredictonlythattheratesofdrug
transferintoandoutofthecompartmentsareequalatsteadystate.Inotherwords,drugconcentrationsinthe
tissuearealsoconstant,butmaydifferfromplasmaconcentrations.
Thetimeneededtoreachasteadystatebloodleveldependsentirelyonthedistributionhalflifeofthedrug.
Theequationdescribingplasmadrugconcentrationasafunctionoftimeisasfollows:

whereaandbarehybridrateconstantsandRistherateofinfusion.Atsteadystate(ie,t=),Equation5.22
reducesto

Byrearrangingthisequation,theinfusionrateforadesiredsteadystateplasmadrugconcentrationmaybe
calculated.

LOADINGDOSEPLUSIVINFUSION:TWOCOMPARTMENTMODEL
Drugswithlonghalflivesrequirealoadingdosetomorerapidlyattainsteadystateplasmadruglevels.Itis
clinicallydesirabletoachieverapidtherapeuticdruglevelsbyusingaloadingdose.However,fordrugsthat
followthetwocompartmentpharmacokineticmodel,thedrugdistributesslowlyintoextravasculartissues
(compartment2).Thus,drugequilibriumisnotimmediate.Theplasmadrugconcentrationofadrugthatfollows
atwocompartmentmodelaftervariousloadingdosesisshowninFigure56.Ifaloadingdoseisgiventoo
rapidly,thedrugmayinitiallygiveexcessivelyhighconcentrationsintheplasma(centralcompartment),which
thendecreasesasdrugequilibriumisreached(Fig.56).Itisnotpossibletomaintainaninstantaneous,stable
steadystatebloodlevelforatwocompartmentmodeldrugwithazeroorderrateofinfusion.Therefore,a
loadingdoseproducesaninitialbloodleveleitherslightlyhigherorlowerthanthesteadystatebloodlevel.To
overcomethisproblem,severalIVbolusinjectionsgivenasshortintermittentIVinfusionsmaybeusedasa
methodforadministeringaloadingdosetothepatient(seeChapter8).

Figure56.

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Plasmadruglevelaftervariousloadingdosesandratesofinfusionforadrugthatfollowsatwocompartmentmodel:a,
noloadingdoseb,loadingdose=R/k(rapidinfusion)c,loadingdose=R/b(slowinfusion)andd,loadingdose=R/b
(rapidinfusion).

ApparentVolumeofDistributionatSteadyState,TwoCompartment
Model
Afteradministrationofanydrugthatfollowstwocompartmentkinetics,plasmadruglevelswilldeclinedueto
elimination,andsomeredistributionwilloccurasdrugintissuediffusesbackintotheplasmafluid.Thevolume
ofdistributionatsteadystate,(VD)SS,isthe"hypotheticalspace"inwhichthedrugisassumedtobe
distributed.Theproductoftheplasmadrugconcentrationwith(VD)SS willgivethetotalamountofdruginthe
bodyatthattimeperiod,suchthatCpSS x (VD)SS =amountofdruginthebodyatsteadystate.Atsteady
stateconditions,therateofdrugentryintothetissuecompartmentfromthecentralcompartmentisequalto
therateofdrugexitfromthetissuecompartmentintothecentralcompartment.Theseratesofdrugtransferare
describedbythefollowingexpressions:

whereDt istheamountofdruginthetissuecompartment.Becausetheamountofdruginthecentral
compartment,Dp,isequaltoVpC p,bysubstitutionintheaboveequation,

Thetotalamountofdruginthebodyatsteadystateisequaltothesumoftheamountofdruginthetissue
compartment,Dt,andtheamountofdruginthecentralcompartment,Dp.Therefore,theapparentvolumeof
drugatsteadystate(VD)SS maybecalculatedbydividingthetotalamountofdruginthebodybythe
concentrationofdruginthecentralcompartmentatsteadystate:

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BysubstitutionofEquation5.27intoEquation5.28,andbyexpressingDp asVpCp,amoreusefulequationfor
thecalculationof(VD)SS isobtained:

whichreducesto

Inpractice,Equation5.30isusedtocalculate(VD)SS.The(VD)SS isafunctionofthetransferconstants,k12
andk21,whichrepresenttherateconstantsofdruggoingintoandoutofthetissuecompartment,respectively.
Themagnitudeof(VD)SS isdependentonthehemodynamicfactorsresponsiblefordrugdistributionandonthe
physicalpropertiesofthedrug,propertieswhich,inturn,determinetherelativeamountofintraand
extravasculardrug.
Anothervolumetermusedintwocompartmentmodelingis(VD)b (seeChapter4).(VD)b isoftencalculated
fromtotalbodyclearancedividedbyb.Unlikethesteadystatevolumeofdistribution,(VD)SS,(VD)b is
influencedbydrugeliminationinthebeta"b"phase.Reduceddrugclearancefromthebodymayincreasethe
areaunderthecurve,AUC,suchthat(VD)b iseitherreducedorunchanged,dependingonthevalueofbas
showninEquation4.30(seeChapter4):

Unlike(VD)b,(VD)SS isnotaffectedbychangesindrugelimination.(VD)SS reflectsthetruedistributional


volumeoccupiedbytheplasmaandthetissuepoolwhensteadystateisreached.Althoughthisvolumeisnot
usefulincalculatingtheamountofdruginthebodyduringpresteadystate,(VD)SS multipliedbythesteady
stateplasmadrugconcentration,CSS,yieldstheamountofdruginthebody.Thisvolumeisoftenusedto
determinetheloadingdrugdosenecessarytouploadthebodytoadesiredplasmadrugconcentration.As
shownbyEquation4.30,(VD)SS isseveraltimesgreaterthanVp,whichrepresentsthevolumeoftheplasma
compartment,butdifferssomewhatinvaluedependingonthetransferconstants.

PracticalFocus
Questions
1.Doyouagreewiththefollowingstatementsforadrugthatisdescribedbyatwocompartment
pharmacokineticmodel?Atsteadystate,thedrugiswellequilibratedbetweentheplasmaandthetissue
compartment,Cp =Ct,andtheratesofdrugdiffusionintoandfromtheplasmacompartmentareequal.
Thesteadystatevolumeofdistributionismuchlargerthantheinitialvolume,Vi,ortheoriginalplasma
volume,Vp,ofthecentralcompartment.Theloadingdoseisoftencalculatedusingthe(VD)SS insteadofV
.
p
2.Azithromycinmaybedescribedbyaplasmaandatissuecompartmentmodel(refertoChapter4).
3."Rapiddistributionofazithromycinintocellscauseshigherconcentrationinthetissuesthanintheplasma.

Page19 of22

..."Doesthisstatementconflictwiththesteadystateconcept?
4.Whyisaloadingdoseused?
Solutions
1.Foradrugthatfollowsamultiplecompartmentmodel,theratesofdrugdiffusionintothetissuesfromthe
plasmaandfromthetissuesintotheplasmaareequalatsteadystate.However,thetissuedrug
concentrationisgenerallynotequaltotheplasmadrugconcentration.
2.Whenplasmadrugconcentrationdataareusedalonetodescribethedispositionofthedrug,no
informationontissuedrugconcentrationisknown,andnomodelwillpredictactualtissuedrug
concentrations.Toaccountforthemassbalance(drugmass/volume=bodydrugconcentration)ofdrug
presentinthebody(tissueandplasmapool)atanytimeafterdosing,thebodydrugconcentrationis
assumedtobetheplasmadrugconcentration.Inreality,azithromycintissueconcentrationismuchhigher.
Therefore,thecalculatedvolumeofthetissuecompartmentismuchbigger(31.1L/kg)thanitsactual
volume.
Theproductofthesteadystateapparent(VD)SS andthesteadystateplasmadrugconcentration(CSS)
estimatestheamountofdrugpresentinthebody.Theamountofdrugpresentinthebodymaybeimportant
informationfortoxicityconsiderations,butmaybeusedasatherapeuticendpoint.Inmostcases,the
therapeuticdrugatthesiteofactionaccountsforonlyasmallfractionoftotaldruginthetissue
compartment.Thepharmacodynamicprofilemaybedescribedasaseparatecompartment(seeeffect
compartmentinChapter19).Basedonpharmacokineticandbiopharmaceuticstudies,thefactorsthat
accountforhightissueconcentrationsincludediffusionconstant,lipidsolubility,andtissuebindingtocell
components.Aratiomeasuringtherelativedrugconcentrationintissueandplasmaisthepartition
coefficient,whichishelpfulinpredictingthedistributionofadrugintotissues.Ultimately,studiesoftissue
drugdistributionusingradiolabeleddrugaremuchmoreuseful.
Therealtissuedruglevelwilldifferfromtheplasmadrugconcentrationdependingonthepartitioningofdrug
intissuesandplasma.(VD)b isavolumeofdistributionoftencalculatedbecauseitiseasiertocalculatethan
(VD)SS.Thisvolumeofdistribution,(VD)b,allowstheareaunderthecurvetobecalculated,anareathat
hasbeenrelatedtotoxicitiesassociatedwithmanycancerchemotherapyagents.Manyvaluesforapparent
volumesofdistributionreportedintheclinicalliteratureareobtainedusingtheareaequation.Someearly
pharmacokineticliteratureincludesonlythesteadystatevolumeofdistribution,whichapproximatesthe(V
) butissubstantiallysmallerinmanycases.Ingeneral,bothvolumetermsreflectextravasculardrug
D b
distribution.(VD)b appearstobemuchmoreaffectedbythedynamicsofdrugdispositioninthebetaphase,
whereas(VD)SS reflectsmoreaccuratelytheinherentdistributionofthedrug.
3.Whendrugsaregiveninamultipledoseregimen,aloadingdosemaybegiventoachievesteadystate
drugconcentrationsmorerapidly.

FREQUENTLYASKEDQUESTIONS
1.WhatisthemainreasonforgivingadrugbyslowIVinfusion?
2.Whydoweusealoadingdosetorapidlyachievetherapeuticconcentrationforadrugwithalong
eliminationhalflife,insteadofincreasingtherateofdruginfusionorincreasingthesizeoftheinfusiondose?
3.WhataresomeofthecomplicationsinvolvedwithIVinfusion?
Answers

LEARNINGQUESTIONS
1.Afemalepatient(35yearsold,65kg)withnormalrenalfunctionistobegivenadrugbyIVinfusion.
Accordingtotheliterature,theeliminationhalflifeofthisdrugis7hoursandtheapparentVD is23.1%ofbody
weight.Thepharmacokineticsofthisdrugassumesafirstorderprocess.Thedesiredsteadystateplasmalevel
forthisantibioticis10 g/mL.
a.Assumingnoloadingdose,howlongafterthestartoftheIVinfusionwouldittaketoreach95%oftheC
?
SS

Page20 of22

b.Whatistheproperloadingdoseforthisantibiotic?
c.Whatistheproperinfusionrateforthisdrug?
d.Whatisthetotalbodyclearance?
e.Ifthepatientsuddenlydevelopspartialrenalfailure,howlongwouldittakeforanewsteadystateplasma
leveltobeestablished(assumethat95%oftheC SS isareasonableapproximation)?
f.Ifthetotalbodyclearancedeclined50%duetopartialrenalfailure,whatnewinfusionratewouldyou
recommendtomaintainthedesiredsteadystateplasmalevelof10 g/mL?
2.Ananticonvulsantdrugwasgivenas(a)asingleIVdoseand(b)aconstantIVinfusion.Theserumdrug
concentrationsareaspresentedinTable5.2.

Table5.2SerumDrugConcentrationsforaHypotheticalAnticonvulsantDrug

ConcentrationinPlasma( g/mL)

Time(hr)

SingleIVDose(1mg/kg)

ConstantIVInfusion(0.2mg/kgperhr)

10.0

6.7

3.3

4.5

5.5

3.0

7.0

2.0

8.0

10

1.35

8.6

12

9.1

18

9.7

24

9.9

a.Whatisthesteadystateplasmadruglevel?
b.Whatisthetimefor95%steadystateplasmadruglevel?
c.Whatisthedrugclearance?
d.Whatistheplasmaconcentrationofthedrug4hoursafterstoppinginfusion?(Infusionwasstoppedafter
24hours.)
e.Whatistheinfusionrateforapatientweighing75kgtomaintainasteadystatedruglevelof10 g/mL?
f.Whatistheplasmadrugconcentration4hoursafteranIVdoseof1mg/kgfollowedbyaconstantinfusion
of0.2mg/kgperhour?
3.AnantibioticistobegivenbyIVinfusion.Howmanymillilitersperminuteshouldasteriledrugsolution
containing25mg/mLbegiventoa75kgadultmalepatienttoachieveaninfusionrateof1mg/kgperhour?
4.Anantibioticdrugistobegiventoanadultmalepatient(75kg,58yearsold)byIVinfusion.Thedrugis
suppliedinsterilevialscontaining30mLoftheantibioticsolutionataconcentrationof125mg/mL.Whatratein
millilitersperhourwouldyouinfusethispatienttoobtainasteadystateconcentrationof20 g/mL?What
loadingdosewouldyousuggest?Assumethedrugfollowsthepharmacokineticsofaonecompartmentopen
model.Theapparentvolumeofdistributionofthisdrugis0.5L/kg,andtheeliminationhalflifeis3hours.
5.Accordingtothemanufacturer,asteadystateserumconcentrationof17 g/mLwasmeasuredwhenthe
antibioticcephradine(Velosef,BristolMeyers,Squibb)wasgivenbyIVinfusionto9adultmalevolunteers
(averageweight,71.7kg)atarateof5.3mg/kghrfor4hours.

Page21 of22

a.Calculatethetotalbodyclearanceforthisdrug.
b.WhentheIVinfusionwasdiscontinued,thecephradineserumconcentrationdecreasedexponentially,
decliningto1.5 g/mLat6.5hoursafterthestartoftheinfusion.Calculatetheeliminationhalflife.
c.Fromtheinformationabove,calculatetheapparentvolumeofdistribution.
d.Cephradineiscompletelyexcretedunchangedintheurine,andstudieshaveshownthatprobenecidgiven
concurrentlycauseselevationoftheserumcephradineconcentration.Whatistheprobablemechanismfor
thisinteractionofprobenecidwithcephradine?
6.CalculatetheexcretionrateatsteadystateforadruggivenbyIVinfusionatarateof30mg/hr.TheCSS is
20 g/mL.Iftherateofinfusionwereincreasedto40mg/hr,whatwouldbethenewsteadystatedrug
concentration,CSS?Wouldtheexcretionrateforthedrugatthenewsteadystatebethesame?Assumefirst
ordereliminationkineticsandaonecompartmentmodel.
7.Anantibioticistobegiventoanadultmalepatient(58yearsold,75kg)byIVinfusion.Theeliminationhalf
lifeis8hoursandtheapparentvolumeofdistributionis1.5L/kg.Thedrugissuppliedin60mLampulesata
drugconcentrationof15mg/mL.Thedesiredsteadystatedrugconcentrationis20 g/mL.
a.Whatinfusionrate,inmillilitersperhour,wouldyourecommendforthispatient?
b.Whatloadingdosewouldyourecommendforthispatient?Bywhatrouteofadministrationwouldyougive
theloadingdose?When?
c.Whyshouldaloadingdoseberecommended?
d.Accordingtothemanufacturer,therecommendedstartinginfusionrateis15mL/hr.Doyouagreewith
thisrecommendedinfusionrateforyourpatient?Giveareasonforyouranswer.
e.Ifyouweretomonitorthepatient'sserumdrugconcentration,whenwouldyourequestabloodsample?
Giveareasonforyouranswer.
f.Theobservedserumdrugconcentrationishigherthananticipated.Givetwopossiblereasonsbasedon
soundpharmacokineticprinciplesthatwouldaccountforthisobservation.
8.Whichofthefollowingstatements(ae)is/aretrueregardingthetimetoreachsteadystateforthethree
drugsbelow.

DrugA DrugB DrugC

Rateofinfusion(mg/hr) 10

20

15

k(hr1)

0.5

0.1

0.05

Cl(L/hr)

20

a.DrugAtakesthelongesttimetoreachsteadystate.
b.DrugBtakesthelongesttimetoreachsteadystate.
c.DrugCtakesthelongesttimetoreachsteadystate.
d.DrugAtakes6.9hourstoreachsteadystate.
e.Noneoftheaboveistrue.
9.Thesteadystatedrugconcentrationofacephalosporinafterconstantinfusionof250mg/hris45 g/mL.
Whatisthedrugclearanceofthiscephalosporin?
10.Someclinicalpharmacistsassumedthat,atsteadystatewhenequilibrationisreachedbetweentheplasma
andthetissue,thetissuedrugconcentrationwouldbethesameastheplasma.Doyouagree?

Page22 of22

Answers

REFERENCES
HurleySF,McNeilJJ:Acomparisonoftheaccuracyofaleastsquaresregression,aBayesian,Chiou'sandthe
steadystateclearancemethodofindividualizingtheophyllinedosage.ClinPharmacokinet14:311320,1988
[PMID:3396259]

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infusion.JPharmSci59:5354,1970[PMID:5411325]
LoughnamPM,SitarDS,OgilvieRI,NeimsAH:Thetwocompartmentopensystemkineticmodel:Areviewofits
clinicalimplicationsandapplications.JPediatr88:869873,1976
MitenkoP,OgilvieR:Rapidlyachievedplasmaconcentrationplateaus,withobservationsontheophylline
kinetics.ClinPharmacolTher13:329335,1972[PMID:5026374]
RiegelmanJS,LooJC:Assessmentofpharmacokineticconstantsfrompostinfusionbloodcurvesobtainedafter
IVinfusion.JPharmSci59:53,1970[PMID:5411325]
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