PHAR6113 Lecture2:Therapeu.

cDrugMonitoring

MasterofPharmacyProgram,UniversityofNewcastle

2011 edition

Learning Outcomes: .............................................................................3 Introduction ...........................................................................................3 Which drugs do we monitor using blood levels? ..............................4 What are indications for TDM testing? ...............................................7 How do we do TDM? .............................................................................7 When do we take samples? .................................................................7 Measuring drug (and metabolite) concentrations: Assay techniques commonly used: ...................................................................................8
HPLC and GC techniques: ................................................................................8 FPIA: ....................................................................................................................9 EMIT .....................................................................................................................9 RIA: ......................................................................................................................9

Comparing different assay methods: ...............................................10 EVALUATING THE ANALYTICAL TECHNIQUES USED AND COLLECTION TECHNIQUES ..............................................................10
Containers used in collecting sample: ...........................................................10 Processing and Storage ..................................................................................11 Sample identication .......................................................................................11 Free or total drug concentration measurements ..........................................11 Analytical technique evaluation: ....................................................................12

Sampling time in TDM ........................................................................13 Factors to consider when interpreting TDM results clinically .......13 Patient age, medical condition and other medication .....................13 Common Errors in TDM interpretation include: ..............................14

Web resources to visit: ......................................................................14 References: .........................................................................................14 Review Questions: .............................................................................14

LearningOutcomes:

Explainthedierentwayswecanmonitordrugtherapy Explainwhatmakesadrugagoodcandidatefortherapeu<cdrug monitoring(measuringblood/plasmalevels) Discussindica<onsforTDM DescribeassaytechniquescommonlyusedinTDMandvalida<onof assays Discussadvantagesanddisadvantagesofdierentassaytechniquesused inTDM Describeinforma<onrequiredforclinicalinterpreta<onofTDMresults

Introduction
Inthepreviouslecture,theconceptsoftherapeu<crangeandtherapeu<cindexwere introduced.Adrugwithanarrowtherapeu.cindexisonewheretheconcentra.onresul.ngin toxicityisclosetotheconcentra.onrequiredtoproducepharmacologicaleect. WealsoexploredthetermkineGchomogeneitywhereweassumeconcentraGonchangesin anaccessibleuidsuchasplasmaorserumwillreectchangesinconcentraGonofthedrugat theactualsiteofeectofthedrug. Measuringplasma/serumdrugconcentraGonsisanimportantpartoftheclinicaluseof pharmacokineGcs.Wecallthismeasurementofdrugconcentra<onsintheclinicalseGng Therapeu<cDrugMonitoring(TDM). IntodayslecturewearegoingtoexploreTherapeuGcdrugmonitoringasoutlinedbelow:

Letsconsidersomeclinicalscenarios. Scenario1: MrsSmithvisitsherGPandherbloodpressureiselevateddespitelosingweightandregular exercise.TheGPisgoingtocommenceheronanan<hypertensivedrugtoreduceherblood pressure.ShedecidestocommencetheMrsSmithonperindoprilanACEinhibitor.Whatis thebestapproachtomonitortheeectofthisdrug?ShouldtheGPmonitorbloodlevels withthisdrug? Scenario2: MrBrowniscommencedonwarfarintoreducecloGngofbloodaVerarecentmyocardial infarct.Heistoldtohaveabloodtesteveryweekun<lthebestdosehasbeenestablished. Dowemonitorbloodlevelsofwarfarin?Whatdowemonitorinthispa<ent? Scenario3: JeanWesthasabipolardisorderandherdoctorwantstocommenceheronlithiumcarbonate tablets.Shouldthispa<enthavetherapeu<cmonitoringofherlithiumbloodlevels? Scenario4: MrElderberryhasheartfailureandisonanumberofmedica<onsforthis.Thedoctordecides tocommencehimondigoxintohelpwithsymptoms.Shouldthispa<enthaveregular monitoringofplasmadigoxinlevels? Inordertoknowthebestac<onforeachofthesescenarios,letslearnsomemoreabout therapeu<cdrugmonitoring.

Whichdrugsdowemonitorusingbloodlevels?
Wedonotmeasurebloodlevelsformanydrugsincommonusesohowdowemonitordrug eectandwhendowemonitorusingbloodlevels? Thereareanumberofwayswecanmonitordrugtherapyanditseects.Theseare:

 bymeasuringorobservingaclinicalresponse byaninvitrotestthatindicatestherapeuGceect bymeasuringblood/plasmaconcentraGonandhavingatargetrange(TDM) Whatsortofclinicalresponsescanwemeasure? IfwehaveapaGentwhohaselevatedbloodpressure,wewillstartthemonanappropriate anGhypertensivedrugandbymeasuringbloodpressurechangesandsideeects,willalter dosingofthedrugtoachieveopGmalbloodpressurereadings.ApaGentswithParkinsons diseasemayrequiredrugssuchasacombinaGonofDOPA/Carbidopa.Wewouldcommencethe paGentonthismedicaGonandwoulddecreasethedoseifwesawdyskinesiasorincreasethe doseifweobserveporrcontrol.Ifweobservedconfusionordepression,thisisasignof possibletoxicity.IfwewereusingadrugsuchasthiopentonetoanaestheiseapaGent,we wouldincreasethedoseifwehaveinsucientanaesthesiaanddecreasethedoseif anaesthesiawastoodeep.Signoftoxicitywouldberespiratoryfailure. Whenwouldweuseaninvitrotestoftherapeu.ceect? Herearesomeexamplesofdrugswherewechangedosebasedonaninvitrotestof therapeuGceect:

Drug

IndicaGon

decreasedose

increasedose

toxicsigns

Warfarin Thyroxine StaGn

TEdisease Hypothyroidism Raisedcholesterol

highINR lowTSH raisedAST/CK

lowINR highTSH highTC

Bleeding Hyperthyroidism Myopathy

Whendoweusemeasurementoflevelsinblood/plasma? WeareusingadrugtotreatpaGentsinaclinicalse]ng.Fromresearchstudies,ithasbeen shownthatthereisagoodcorrelaGonbetweenconcentraGonofdruginplasmaandtheeect wewanttoachieve.FromthestudieshoweverweseethatthedrughasanarrowtherapeuGc index.TheminimumeecGveconcentraGonformostpaGentsis2mcg/mLandweseetoxicityin manypaGentswhenwegoabove4mcg/mL.AddiGonally,thetoxiceectsareseriousandcan harmthepaGentsoavoidingtoxicityisessenGal.Tomakedosingmoredicult,whenwe administer50mgdosestoallpaGentsweseedramaGcdierencesinbloodlevelsachievedand somepaGentsshownoresponse,someshowresponseandsomeshowsignsoftoxicity.We havewideinterindividualvariabilityinbloodlevelsachievedwiththeSAMEdose. Thisdrugisagoodcandidatefortherapeu<cdrugmonitoring

AnexampleoftheuseofTDM: PriortouseofTDM,phenytoinwasprescribedempiricallyasa300mgdailydose.PaGents eitherresponded,showedsideeectsordidnotrespond(sGllhadseizures).Withtheadventof monitoring,itwasfoundthatwhenthisdoseisadministeredinalargegroupofpaGents,there isagreaterthan10foldvariaGoninplasmadrugconcentraGonsobservedinthesepaGentsas showninplotbelow.

WithTDM,itispossibletoindividualisedosesandnowdosesbetween150700mg/dayarenow used.Theadvantageofphenytoinmonitoringisbeingabletonelyadjustdoseonanindividual basisforadrugthatshowslargevariabilityinpharmacokineGcs.ThemeasureofeecGveness ofthisdrugiscessaGonof]ngnotaneasypharmacologicaleecttoquanGfy.Researchwork hasalsowellestablishedtheopGmumrangeofbloodconcentraGons(therapeuGcrange).This drugisevenmorecomplicatedtoadjustdosethanusualasdrugshowsnonlinearkineGcs.We willdiscussnonlinearkineGcsinfuturelectures. RememberwithTDM,plasmaconcentraGonsalwaysactasaguideandareusedinconjuncGon withclinicalobservaGonsandresponse.RememberthatasmallpercentageofpopulaGonare likelytoshowadverseeectswithinthetherapeuGcrangewhilesomemayrequirehigher concentraGons.Manyresponsesaregradedeecttoxiceectsdonotjustmagicallyand suddenlyappearusuallyadverseeectsarealsoagradedresponse. Tosummarise,monitoringisgenerallydonefordrugswhich: haveanarrowtherapeuGcindex, havelargeinterindividualvariaGoninpharmacokineGcs toxiceectsaredramaGcand forwhichthereisgoodcorrelaGonbetweeneectandconcentraGonandatherapeuGc rangehasbeendetermined. Wherewillyouseetherapeu0cdrugmonitoringusedineverydayprac0ce? Herearesomecommonexamples AminoglycosidesusedtotreatseriouslifethreateninginfecGons Drugssuchasgentamicinmayproducenephrotoxicity(damageotkidneys)andototoxicity(loss ofhearing).ThereisarelaGonshipbetwenconcentraGonsachievedandeectandtoxicity. An<epilep<cdrugssuchaphenytoinwherethedesiredeectissuppressionofepilepGc seizures.(aswesawintheexampleabove)

DigoxinisusedincardiaccondiGonssuchasheartfailureandatrialbrillaGon.Thereisa denedtherapeuGcrange.ThisdrugcanshowmarkedinterindividualvariaGoninbloodlevels achievedatthesamedose.Signsoftoxicityincludenonspeciconessuchasnausea,vomiGng, abdominalpainandconfusion,butcanalsohaveseriouscardiaceect. LithiumisusedintreaGngbipolardisorders.IthasanarrowtherapeuGcindex.Thereiswide interindividualvariaGoninplasmalevelsachieved.Signsoftoxicitycanrangefromtremorto ataxiaanddiarrhoeatoconvusionsandts. Nowtakeamomenttoconsiderthe4casescenariosatthebeginningofthislecture.Which oneswouldrequiretherapeu<cdrugmonitoringandwhy?

Whatareindica<onsforTDMtes<ng?
Drugecacydiculttoestablishclinically(eganGconvulsanteectofPhenytoin) Suspectedtoxicity(clinicalsignsinpaGent) inadequatetherapeuGcresponseinpaGent paGentcompliancewithmedicaGon? dosagechange changeinclinicalstatusofpaGent changeinothermedicinesbeingcoadministered(egQuinidinereducesclearanceofDigoxin)

WhenisTDMnotindicated: whenwehaveadrugwheretoxicityisnotarealisGcconcern(egPenicillins) eectscanbemeasuredusingafuncGonallabtest(egwarfarin) Plasma/blooddrugconcentraGonsnotrelatedtoeects(egwarfarin) eectrelaGonshiphasnotbeendened

HowdowedoTDM?
Biologicaluidsamples(usuallyblood/plasma/serum/urineorsaliva)iscollectedfrompaGent receivingthedrugwewishtomonitor.Thissample(orsamples)areanalysedusingan appropriateassaymethodtodeterminedrugconcentraGon.

Whendowetakesamples?
UsuallythepaGentwilltakethedrugforsucientGmetoreachwhatwetermsteadystate. Timingofsampleisusuallyjustbeforethenextdose(calledtroughsamples). ToillustratewhatwemeanbytroughandpeakconcentraGons,lookattheplotbelow.Thisis whathappensaswestarttoadministerregulardosesofadrugtoapaGent.Wewillseearisein

bloodlevelsonconGnuedadministraGonunGlwegettoaplateau.Ideallywewantbloodlevels toplateauinthetherapeuGcrange.

Measuringdrug(andmetabolite)concentra<ons:Assay techniquescommonlyused:
FPIA(uorescencepolarisaGonimmunoassaytechniques RIA(radioimmunoassay) EMIT(enzymemulGpliedimmunoassaytechnique) HPLC(highperformanceliquidchromatography) GC(gaschromatography)

HPLC and GC techniques: ChromatographyinvolvesseparaGonofcomponentsinasampleontheirsolubilityinmobile andstaGonaryphases.Commonlyusedchromatographymethodsaregaschromatographyand liquidchromatography(HPLC).WithchromatographyseparaGons,amobilephaseispumped throughastaGonaryphase.Compounds(drugsandendogenoussubstances)willparGGonto varyingextentsdependingonmoleculeproperGesbetweenthemobilephaseandstaGonary phase.

HPLC: Mobilephaseispumpedthroughacolumnofpackedmaterial(athighpressure.Thesampleis injectedintothestream.Ifthedruglikesthepacking,itwilltakelongerthanothercompounds insampletoelutefromcolumn.Whendrugelutesfromthecolumn,itpassesthrougha

detectorwhichmeasurestheamountofdrugeluGng.Dierenttypesofdetectorsmaybeused includingUV,electrochemical,uorescenceandMassspectrometry. HerearesomelinkstousefulwebsitesonHPLC:Takeamomenttoviewthesepages hkp://www.waters.com/waters/nav.htm?cid=10048919&locale=en_US hkp://www.youtube.com/watch?v=ICdTU5X4HA GasChromatography(GC): GCisasimilarprinciplewiththemobilephasebeinggasnotaliquid.VerysensiGvetechniques employmassspectrometryasdetector. Hereisalinktoresourcesexplaininggaschromatography: hkp://www.youtube.com/watch?v=deiLgeKx8 FPIA: (FPIA)isatechniquewhichtakesadvantageoftheincreasedpolarizaGonofuorescentlight emissionswhenauorescentlylabeledanGgenisboundbyreagentanGbody.Thehigherthe concentraGonofunlabeledpaGentanGgenpresentinthetestmixture,thelessbound uorescentanGgenispresentand,consequently,thelowerthepolarizaGonoftheuorescent lightemission. LabelledanGgen(inotherwordsdruglabelledwithauorophore)isaddedtothesampleyou wishtoassay.AnGbodyisalsoaddedtothesample.Thedruginthebiologicalsamplecompetes withthelabelleddrugfortheanGbody.Ifthereislikledrugpresentinthebiologicalsample, theaddedlabelleddrugwillbindtoanGbodyandtherewillbehigherpolarizaGon(higher readings).Ifalotofdrugispresent,likleofthelabelleddrugwillgetakachedtoanGbodiesand sowewillseealowerreading.Byusingsampleswithknownamountsofdrug,acalibraGon curveisproducedandtheresultoftheclinicalsamplecanbereadothecalibraGoncurve. Herearesomeusefullinks: hkp://www.boomer.org/c/p3/c03/c0309.html EMIT Thisisaprocedureinwhichthedrugbeingmeasuredcompetesforalimitednumberof anGbodybindingsiteswithenzymelabelleddrug.Toabiologicalsampleisaddeddruglabelled withenzymeandanGbodytothedrug.Onlyenzymewhichisnotlinkedtoboththedrugand anGbodycanreactwithanaddedsubstrate.(TheanGbodyhastheabilitytoblockenzymaGc acGvitywhenboundwiththereagentenzymedrugcomplexprevenGngit'sformaGonof productinthepresenceofsubstrate).Asubstratefortheenzymeisaddedandacolorchangeis produced.ThiscolourchangeisproporGonaltotheconcentraGonofdrugpresentinthe specimen. RIA: Thedrugsample,labelleddrugandanGbodytodrugaremixedandincubated.Thebounddrug (bothlabelledandunlabelledfromsample)areseparatedandtheradioacGvitycounted.The

moredrugintheactualsampleadded,thelesstheradioacGvityreadingaslessoftheadded labelleddrugcanbindtotheanGbodiespresent

Comparingdierentassaymethods:

TechniquesinvolvinguseofanGbodyanGgeninteracGonsmayshowcrossreacGvity. Herearesomeusefulwebsitestolookat: hkp://www.clinchem.org/cgi/content/full/48/3/507 hkp://books.google.com.au/books?id=1bv0cvkxklsC&pg=PA146&lpg=PA146&dq=digoxin+ +interference&source=bl&ots=vKs7bNdpZq&sig=0whutGcgt8otFy YPRQnVKquVg&hl=en&ei=FG4eTYijJo3RccavmOgK&sa=X&oi=book_result&ct=result&resnum=7 &ved=0CEMQ6AEwBjge#v=onepage&q=digoxin%20%20interference&f=false

EVALUATINGTHEANALYTICALTECHNIQUESUSEDAND COLLECTIONTECHNIQUES
Containersusedincollec<ngsample: ThetypesoftubesintowhichbloodiscollectedcanbeasourceofproblemsinTDMtesGng.For example,therehavebeenreportsofchemicalsleachingfromrubberstoppersintubescausing

problemswithassays.SometubescontaingelbarriersserumseparaGngtubesandthisgel barrierhasbeenreportedtoadsorbquiteafewdrugs.Theamountofadsorbeddependedon Gmeofcontact,theamountofsample,drugconcentraGonpresentinvial,temperatureand lengthofstorage.Inotherinstances,chemicaladdiGvesaddedtoenhanceclo]ngorprevent adsorpGonintotubesorplasGciserspresenthavebeenfoundtointerferewithanalyses. ItisthereforeessenGalthatthesamplesarecollectedintothecorrecttypeoftube. Laboratorieswillusuallyspecifythetypeoftuberequired. VisitthewebsitebelowforHAPSandseewhattheyspecifyfordrugssuchasdigoxin,lithium andphenytoin hkp://www.haps.nsw.gov.au/Handbook/hh02.aspx?test=197 ProcessingandStorage Itshouldneverbeassumedthatonceasampleiscollected,thedrugwillbestableinthetube. Blood,plasmaandserumarecomplexmatricesandsamplesshouldbetestedassoonas possibleayercollecGon.IftheycannotbeassayedrelaGvelyquickly,samplesshouldbe appropriatelyhandled(usuallycentrifugedtosparateplasma/serum)andthenrefrigeratedor frozen.Asanexample,paGentsongentamicinareoyenonotheranGbioGcssuchasbeta lactams.WeavoidcomixingandadministraGonofthesedrugsbecausetheyinacGvateeach other,sowhentheyareadministeredoneisgivenandthentheotherisgivensotheydonot physicallymix.Forthelaboratorythismeansthatbothdrugsarepresentinthebloodsample.if thebloodsampleisleyatroomtemperatureandbothdrugsarepresentinthesample,then theaminoglycosideconcentraGonwilldeclinesignicantlyataratedependentonthe aminoglycosideandthebetalactampresentaswellasGmeandtemperatureofexposure. Becausewedonotknowifbotharepresentandtowhatextent,thesesamplesshouldbe separated(spindownincentrifuge)andanalysedassoonaspossibleorfreezesampleiftesGng isdelayed. Sampleiden<ca<on TubescontainingsamplesmustbeclearlylabelledwithpaGentIDdetailsANDtheGmeof collecGonasthisiscriGcalininterpreGngtheresultobtained.Thisalsohelpsreducepossible errorsinmixingupresultsbetweenpaGents. Freeortotaldrugconcentra<onmeasurements FormostdrugsweobtainatotaldrugconcentraGoninthebloodorplasma/serumfromthe TDMlab.OccasionallyafreeorunbounddrugconcentraGonwillbereported. WhatwemeanbytotaldrugconcentraGonisthatboththeunbounddrugandbounddrugin theplasmaorbloodismeasured.Drugcanbeboundtoplasmaproteinsorothercomponents inthebloodorplasmaaswellasunboundorfree. Inmostcases,wemeasurethetotalconcentraGonastheraGobetweentotalandfree concentraGonwillbeconstant.However,occasionally,therelaGonshipbetweenfreeandtotal concentraGonisextremelyvariableamongpaGentsormaybealteredduetodiseasestatesor interacGonswithotherdrugs.Inthesecases,freedrugconcentraGonsaremeasured.Measuring freedrugconcentraGonrequiresspecialisedequipmentandtechniques.

OnetechniqueusedisultraltraGon.Withthistechnique,theplasmaorserumcontainingboth freeandbounddrugisplacedinadevicewhichcontainsamembrane.Thedeviceiscentrifuged foracertainperiodofGme.Themembranedoesnotallowplasmaproteintopassthroughbut druginextracellularwater(unbound)cangothrough.Theultraltrateisthenassayedto determinethefreedrugconcentraGon. Analy<caltechniqueevalua<on: InordertobeabletocondentlyuseresultsobtainedfromaTDMassay,itisessenGalthatwe haveanassaywhichmeetsappropriatecriteria.Theresultobtainedisonlyasgoodastheassay techniqueused. Anassaymustbeaccurate,precise,reproducible,specicandsucientlysensiGveforthedrug wearewanGngtoanalyse.Wewillnowreviewtheseconcepts. Accuracy,PrecisionandSpecicity WeneedtoensurethatourassayisgivinguscorrectresultseachandeveryGmewerunthe assayiethattheresultsareaccurateandreproducible.Wealsoneedtoensurethatweare actuallymeasuringthedrugofinterestandonlythis. Accuracyishowclosethemeantestresultobtainedcomestothetruevalue.Accuracyis generallydeterminedusingaminimumof5determinaGonsperconcentraGoninthe appropriatematrix.Ideallyweshouldseelessthan5%variaGoninresultsobtained. Precisiondescribestheclosenessofindividualmeasuresofdrugtoeachotherwhenwehave repeatedassayofasample.Thisshouldbedeterminedusingaminimumof5determinaGons perconcentraGon.Thisshouldideallybe36%andnotexceed10%atlowerlimitof quanGtaGon. Generallywewouldtestaccuracyandprecisionbyrunning4or5replicatesampleson4or5 occasionsandthenstaGsGcallyanalysingtheresults. Specicity: Ourassayshouldonlymeasurethedrugofinterest.SomeGmestherewillbesubstancesthat willleadtoafalseincrease(ordecrease)inthedrugconcentraGonwemeasure.Forexample withimmunoassaymethods,becauseweuseanGbodiesthatmaycrossreactwithmetabolites ordrugswithsimilarchemicalstructuresorevenendogenouscompounds,wemaygetfalsely elevatedconcentraGons.Falsehighlevelsbeingreportedcanleadtoadecreaseindosewhen infactthelevelsweactuallyhavepresentareappropriate.Decreasingdosemayproduce therapeuGcfailure.Afalselylowvaluemayleadtoincreasingdosewhenthisisnotneededand consequentlymayproducetoxiceects. QUALITYcontrolsamples: Sampleswithaknownamountofdrugshouldalsobeincludedintheassayrun.Ifthesevalues falloutsidecertaindenedrange,theassayshouldberejected.TDMlabswilloyenparGcipate inexternalqcprogramwheresamplessuppliedbyanexternallabareassayedinrouGneassays

performedandresultssenttoexternallab.Reportsreceivedbackassistindeterminingwhether assayisperformingcorrectly.

Sampling<meinTDM
Generally,wetakebloodsamplesforanalysisoncepaGenthasreachedsteadystate.When paGentsreceivedrugsatspeciedintervals,ayer4to5halflivesforthedrug,theplasma concentraGonsinthepaGentwillplateauandthisplateauiswhatwecallsteadystate.Itis commontomeasuretroughlevelsorconcentraGonsinpaGentsatsteadystate.Thisisthe concentraGonjustbeforethenextdoseisgiven.ManytherapeuGcrangeshavebeen determinedbasedontroughdrugconcentraGons.Thisisusuallybecauseitisdicultto determineexactlywhenpeakplasmaconcentraGonswillbeachievedinapaGent.Forexample, rateofabsorpGonofadruggivenorallymayvarypeakmayoccurat1hourforpaGentand perhaps2hoursinanother.ItmayevenvarywithinthesamepaGentdependingonfor examplethetypeofmealingestedwiththemedicaGon.Troughlevelsproducemuchmore consistentvalues.

Factorstoconsiderwheninterpre<ngTDMresultsclinically
Pa<entCompliance: FactorsaecGngcomplianceincludecostofmedicaGon,mulGpledailydoses,dicultin swallowing,adversedrugreacGonsandcomplicatedinstrucGons.Itisimportanttogainan accuratehistoryofdosinginordertointerpretresults. ieDowehaveanaccuratedosingpicture?

Pa<entResponse: HasthepaGentrespondedtothetreatment?(eglackofseizures,therapeuGceectobserved) Assayandsamplecollec<on/handling: Whattypeofanalysiswasused?.Arethereanyfactorstobeconsideredegdosomedisease statesinterferewiththeassaygivingerroneousresults,willotherdrugspaGentistaking potenGallyinterferetocauseafalseelevaGonordecreaseinconcentraGonobtained?Was samplecollectedandhandledcorrectly(asdiscussedearlierinlecture)? Timingofsample: IfdrugwastobetroughconcentraGon(iejustbeforenextdose);wassamplecollectedat correctGme? Pa<entage,medicalcondi<onandothermedica<on Ifdoseadjustmentisindicatedwhenconsideringresult,checkingwhetherothermedicaGon mayhaverecentlybeencommencedthatmaybeinteracGngtoproducehigherorlowerlevels; haspaGentseliminaGonofdrugchangedduetoillnessshouldalsobeconsidered.

CommonErrorsinTDMinterpreta<oninclude:
FailureofthecliniciantoappreciatethepracGcallimitaGonsofthetherapeuGcrange InappropriatesamplingGmeinrelaGontodose FailuretounderstandthepotenGaleectofdiseasestateondrugconcentraGons observed FixedbeliefinsuperiorityofbiochemicaloverclinicaldataieconcentraGngtoomuchon thelabresultandnotassessingclinicalresponseaswell

Webresourcestovisit:
www.medical.siemens.com/siemens/.../TDM/TDM_Guide_FINAL.pdf hkp://ajcp.ascpjournals.org/content/118/1/132.full.pdf hkp://www.nes.scot.nhs.uk/prescribing/topics/TDM/page16.htm

References:
Shargel,PuWongandYu(2004)AppliedBiopharmaceuGcsandPharmacokineGcsMcGrawHill RowlandMandTozerT(1995)ClinicalPharmacokineGcs:ConceptsandapplicaGon3rdediGon Lippincok,WilliamsandWilkins TozerTandRowlandM(2006):IntroducGontoPharmacokineGcsandPharmacodynamics:The QuanGtaGveBasisofdrugTherapy.LippincokWilliamsandWilkins BirkekDJ(2002)PharmacokineGcsmadeeasy(revised).McGrawHill DiPiroetal(2002)ConceptsinClinicalPharmacokineGcs3rdediGonASHP

ReviewQues<ons:
1. DescribefourfactorswhichmakeadrugagoodcandidateforTDM 2. Whenwouldwejustmonitorclinicalresponseandnotplasma/bloodconcentraGons? 3. WhenwouldwemonitorinvitrotherapeuGceectratherthantheplasma/blooddrug concentraGon? 4. Brieydescribeeachofthefollowingtypesofassayshowtheywork:FPIA;HPLCand GC;EMIT;RIA

5. Writeasummaryoftheadvantagesanddisadvantagesofeachofthesetechniques listedabove 6. ExplainthedierencebetweenmeasuringtotaldrugconcentraGoninasampleandfree drugconcentraGon 7. DiscussfactorsthatneedtobeconsideredwhenevaluaGngtheassaytechniqueusedin TDM 8. WhatdowemeanbyQualityControlsamples? 9. DiscussfactorsthatneedtobeconsideredwheninterpreGngTDMresultsclinically 10. Discusswhythewaythesampleiscollectedandhandledisimportant 11. ListsomedrugsforwhichTDMisperformed SELFASSESSMENTTASK: GOOD ExplainingwhenweuseTDMandwhenwedo not Discussingfactorsthatmakedruggood candidateforTDM Describingprinciplesofdierentassay techniquesused Discussingadvantagesanddisadvantagesof dierentassaytechniques(compare/contrast methods) DiscussfactorstoconsiderwhenevaluaGngthe assaytechniqueused DiscussfactorstoconsiderwheninterpreGng resultsfromTDMlaboratory DiscusssamplingGmesandsamplehandling ListdrugsforwhichTDMiscommonlyused FAIR POOR