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IDENTIFICATIONANDQUANTIFICATION OFDRUGS,METABOLITES, DRUGMETABOLIZINGENZYMES, ANDTRANSPORTERS Concepts,Methods,andTranslationalSciences
IDENTIFICATIONAND QUANTIFICATION OFDRUGS, METABOLITES,DRUG METABOLIZING ENZYMES,AND TRANSPORTERS Concepts,Methods,and TranslationalSciences Editedby SHUGUANG MA SWAPAN K.CHOWDHURY
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Contributors FarahAlQaraghuli DepartmentofPharmaceuticalSciences,SchoolofPharmacyand PharmaceuticalSciences,TheStateUniversity ofNewYorkatBuffalo,Buffalo,NY,United States
RavindraVarmaAlluri ClinicalPharmacology andSafetySciences,R&DBioPharmaceuticals, AstraZeneca,Cambridge,UnitedKingdom
SophieM.A.Argon DepartmentofPharmaceutics,SchoolofPharmacy,Universityof Washington,Seattle,WA,UnitedStates
PiyushBajaj DrugSafetyResearchandEvaluation,TakedaPharmaceuticalInternationalCo., Cambridge,MA,UnitedStates
TashingaE.Bapiro DMPK,ResearchandEarly Development,OncologyR&D,AstraZeneca, Cambridge,UnitedKingdom
AbdulBasit DepartmentofPharmaceutics, UniversityofWashington,Seattle;DepartmentofPharmaceuticalSciences,Washington StateUniversity,Spokane,WA,UnitedStates
AndreasBrink RochePharmaResearch andEarlyDevelopment,RocheInnovation CenterBasel,F.Hoffmann-LaRocheLtd,Basel, Switzerland
TingtingCai LaboratoryTestingDivision, WuXiAppTec,Nanjing,China
JoseCastro-Perez AgiosPharmaceuticals,Inc., Cambridge,MA,UnitedStates
JaeH.Chang PreclinicalDevelopment,ORIC Pharmaceuticals,SouthSanFrancisco,CA, UnitedStates
EugeneChia-TeChen DepartmentofDrug MetabolismandPharmacokinetics,Genentech, SouthSanFrancisco,CA,UnitedStates
MarieCroft PharmaronABS,Germantown, MD,UnitedStates
LiamEvans HyphaDiscoveryLtd.,Oxfordshire,UnitedKingdom
RaymondEvers DepartmentofPharmacokinetics,PharmacodynamicsandDrugMetabolism, Merck&CoInc.,Kenilworth,NJ,UnitedStates
RobertS.Foti Pharmacokinetics,PharmacodynamicsandDrugMetabolism,Merck ResearchLaboratories,Boston,MA,United States
AdrianJ.Fretland DMPK,ResearchandEarly Development,OncologyR&D,AstraZeneca, Waltham,MA,UnitedStates
ChristopherGemski TranslationalResearch BioassayandImmunogenicityGroup,Drug MetabolismandPharmacokineticDepartment, TakedaPharmaceuticalsInternationalCo., Cambridge,MA,UnitedStates
AnimaGhosal IndependentConsultant, Piscataway,NJ,UnitedStates
JiaHao DrugMetabolism,GileadSciences Inc,FosterCity,CA,UnitedStates
SatyajeetHaridas TranslationalResearchBioassayandImmunogenicityGroup,Drug MetabolismandPharmacokineticDepartment, TakedaPharmaceuticalsInternationalCo., Cambridge,MA,UnitedStates
SimonHauri RochePharmaResearchandEarly Development,RocheInnovationCenterBasel, F.Hoffmann-LaRocheLtd,Basel,Switzerland
NinaIsoherranen DepartmentofPharmaceutics,UniversityofWashington,Seattle, WA,UnitedStates
WenyingJian DMPK,JanssenR&D,Spring House,PA,UnitedStates
KevinJohnson DrugMetabolismandPharmacokinetics,Genentech,SouthSanFrancisco, CA,UnitedStates
BarryJones DMPK,ResearchandEarlyDevelopment,OncologyR&D,AstraZeneca,Cambridge,UnitedKingdom
RobertS.Jones DrugMetabolismandPharmacokinetics,Genentech,SouthSanFrancisco, CA,UnitedStates
JanFelixJoseph FreieUniversitaetBerlin,InstituteofPharmacy—PharmaceuticalAnalysis; FreieUniversitaetBerlin,Departmentof Biology,Chemistry,Pharmacy,CoreFacility BioSupraMol,Berlin,Germany
S.CyrusKhojasteh DrugMetabolismand Pharmacokinetics,Genentech,SouthSan Francisco,CA,UnitedStates
YurongLai DrugMetabolism,GileadSciences Inc,FosterCity,CA,UnitedStates
HoaLe DrugMetabolism,GileadSciences, FosterCity,CA,UnitedStates
XiaominLiang DrugMetabolism,GileadSciencesInc,FosterCity,CA,UnitedStates
LimingLiu ProductDevelopment,Curon BiopharmaceuticalLtd,Shanghai,People’s RepublicofChina
FilipeLopes RochePharmaResearchand EarlyDevelopment,RocheInnovationCenter Basel,F.Hoffmann-LaRocheLtd,Basel, Switzerland
JustinQ.Ly DrugMetabolismandPharmacokinetics,Genentech,SouthSanFrancisco,CA, UnitedStates
ShuguangMa DrugMetabolismandPharmacokinetics,GenentechInc.,SouthSanFrancisco, CA,UnitedStates
RoshiniMarkandu DMPK,ResearchandEarly Development,OncologyR&D,AstraZeneca, Cambridge,UnitedKingdom
RosalindeMasereeuw DivisionofPharmacology,UtrechtInstituteforPharmaceutical Sciences,Utrecht,TheNetherlands
J.EricMcDuffie Investigative&Mechanistic Toxicology,JanssenResearch&Development, SanDiego,CA,UnitedStates
KaushikMitra DepartmentofDrugMetabolismandPharmacokinetics,JanssenResearch andDevelopment,Springhouse,PA,United States
DianaMontgomery DepartmentofPharmacokinetics,PharmacodynamicsandDrug Metabolism,Merck&CoInc.,Kenilworth,NJ, UnitedStates
AlexandraL.Orton DMPK,ResearchandEarly Development,OncologyR&D,AstraZeneca, Cambridge,UnitedKingdom
KatieH.Owens DepartmentofPharmaceutics, SchoolofPharmacy,UniversityofWashington,Seattle,WA,UnitedStates
AxelPahler RochePharmaResearchand EarlyDevelopment,RocheInnovationCenter Basel,F.Hoffmann-LaRocheLtd,Basel, Switzerland
MariaKristinaParr FreieUniversitaetBerlin, InstituteofPharmacy—PharmaceuticalAnalysis,Berlin,Germany
ShefaliPatel DMPK,JanssenR&D,Spring House,PA,UnitedStates
IchikoD.Petrie DepartmentofPharmaceutics,SchoolofPharmacy,Universityof Washington,Seattle,WA,UnitedStates
RichardPhipps HyphaDiscoveryLtd.,Oxfordshire,UnitedKingdom
ChandraPrakash AgiosPharmaceuticals,Inc., Cambridge,MA,UnitedStates
BhagwatPrasad DepartmentofPharmaceutics, UniversityofWashington,Seattle;Department ofPharmaceuticalSciences,WashingtonState University,Spokane,WA,UnitedStates
IsabelleRagueneau-Majlessi Departmentof Pharmaceutics,SchoolofPharmacy,UniversityofWashington,Seattle,WA,UnitedStates
VenkateshPillaReddy DMPK,Researchand EarlyDevelopment,OncologyR&D;DepartmentsofModelingandSimulation,Early OncologyDrugMetabolismandPharmacokinetics,R&DOncology,AstraZeneca, Cambridge,UnitedKingdom
EllenRiddle DrugMetabolism,GileadSciences Inc,FosterCity,CA,UnitedStates
QianRuan PharmaceuticalCandidateCharacterization,Bristol-MyersSquibb,Princeton, NJ,UnitedStates
SimoneSchadt RochePharmaResearchand EarlyDevelopment,RocheInnovationCenter Basel,F.Hoffmann-LaRocheLtd,Basel, Switzerland
DhavalK.Shah DepartmentofPharmaceutical Sciences,SchoolofPharmacyandPharmaceuticalSciences,TheStateUniversityofNew YorkatBuffalo,Buffalo,NY,UnitedStates
JuliaShanu-Wilson HyphaDiscoveryLtd., Oxfordshire,UnitedKingdom
KellyMacLennanStaiger DrugMetabolism, GileadSciencesInc,FosterCity,CA,UnitedStates
JonathanSteele HyphaDiscoveryLtd.,Oxfordshire,UnitedKingdom
ManthenaV.S.Varma MedicineDesign, WorldwideR&D,PfizerInc.,Groton,CT, UnitedStates
MatthewP.Wagoner DrugSafetyResearch andEvaluation,TakedaPharmaceuticalInternationalCo.,Cambridge,MA,UnitedStates
NaidongWeng DMPK,JanssenR&D,Spring House,PA,UnitedStates
StephenWrigley HyphaDiscoveryLtd., Oxfordshire,UnitedKingdom
CaishengWu SchoolofPharmaceuticalSciences,XiamenUniversity,Xiamen,China
GraemeC.Young GlaxoSmithKlineResearch andDevelopmentLtd.,DavidJackCentre, Ware,UnitedKingdom
JingjingYu DepartmentofPharmaceutics, SchoolofPharmacy,UniversityofWashington,Seattle,WA,UnitedStates
LushanYu InstituteofDrugMetabolismand PharmaceuticalAnalysis,ZhejiangUniversity, Hangzhou,People’sRepublicofChina
SuZeng InstituteofDrugMetabolismand PharmaceuticalAnalysis,ZhejiangUniversity, Hangzhou,People’sRepublicofChina
HaeyoungZhang DepartmentofPharmaceutics,UniversityofWashington,Seattle, WA,UnitedStates
WanyingZhang DepartmentofPharmaceuticalSciences,SchoolofPharmacyand PharmaceuticalSciences,TheStateUniversityofNewYorkatBuffalo,Buffalo,NY, UnitedStates
AndyZ.X.Zhu DepartmentofDrugMetabolismandPharmacokinetics,TakedaPharmaceuticalsInternationalCo.,Cambridge,MA, UnitedStates
MingsheZhu MassDefectTechnologies,Princeton,NJ,UnitedStates
Foreword Itismygreatpleasuretowritetheforewordforthisexcellentbook.Thestudyof drugmetabolismanddispositionisamature science,butstillessentialindrugdiscovery anddevelopment.Indeed,aquicksearchof PubMed,using“drugmetabolism”asthe searchterm,cameupwithmorethan 18,000hits.Oneoftheearlierarticlesisby BernardBrodie,consideredtobethefounder ofmodernpharmacologyandamajorcontributortothestudyofdrugmetabolism. Hisarticle—publishedintheJournalofPharmacyandPharmacologyin1956—istitled “PathwaysofDrugMetabolism”anditisbased onalectureattheUniversityofLondon [1] Itdescribeshisworkoverthedecadeand someofitisbasedoncollaborationswith otherpioneersinthefieldsuchasJulius Axelrod.Onesentencestillresonatesvery muchanditactuallycoversmuchofthematerialdescribedinthisbook:
Finally,itisthoughtthatadetailedknowledgeofenzymesinvolvedindrug“detoxification”mighthelpthemedicinalchemistto developcompoundsofeitherhighorlowstabilityinthebody,whicheverwouldbemoredesirableingainingadesiredtherapeuticresult.
Drugmetabolismscienceshaveadvanced tremendouslysincethepublicationofthisarticleandthisprogresswastoalargeextent enabledbyadvancesintheavailabilityof biochemicalreagentsandbioanalyticaltechniques,inparticularmassspectrometry. Bothacademicandindustrialscientistshave
identifiedmanybreakthroughsthathave ultimatelycontributedtobringingdrugsto patientswithanurgentneedforbettertreatments.Itisverygratifyingthatthenumber ofdrugsapprovedbytheFDAisincreasing steadilywith38NMEs(newmolecularentity)and10BLAs(biologicallicenseapplication)approvedbytheUSFoodandDrug Administration(FDA)in2019 [2].Thelevel ofinnovationisbestillustratedbyabouthalf oftheapproveddrugsin2019havinga breakthroughdesignation.Drugmetabolism andpharmacokinetics(DMPK)scientistsare fullyembeddedinprojectteamsindrugdiscoveryandworkhandinhandwithmedicinalchemistsontheidentificationofdrugs withsuperiorproperties.Thesescientists havebecomeverygoodatdialingoutthe “knownunknowns”suchasmetabolismbycytochromeP450enzymes.However,thishas actuallyresultedinhavingtodealwithmuch morecomplexdrugdispositionpathwaysinvolvinglesswell-studieddrugmetabolizing enzymesandalsomoreandmoredrug transporters.Thistrendisalsofueledbya shifttowardmoreandmoredrugshaving beyondthe“ruleoffive”molecularproperties [3].Indeed,theaveragemolecular weightofdrugsapprovedbytheFDAin 2016and2017wasmorethan500Daand themedianclogPofdrugsapprovedfrom 2008to2017isnow3.3,inpartdrivenbytrying,forexample,todisruptprotein-protein interactions.Anadditionalconsequenceof thisshiftinpropertiesisthatinvitroto invivoextrapolationofADMEproperties
topredictthehumanpharmacokineticshas becomemorecomplexandthesamecanbe saidofpredictingdrug-druginteraction— manyofwhichnowinvolvedrugtransporters.Ifanything,theinvolvementof DMPKscientistsisnowmoreimportantthan everbecauseofthepursuitofnovelmolecular modalitiesinacademiaandinthepharmaceuticalindustry;afewthatcometomind areantibody-drugconjugates,proteindegraders,andmacrocyclicpeptides.DMPK scientistscanhelpmakedrugsoutofthese hard-to-drugmodalities.Finally,theintegrationofthisdiversearrayofinvitroandinvivo dataisenabledbycomputationalmodeling andsimulation.Physiologicallybasedpharmacokinetic(PBPK)modelingisaverypowerfultooltopredicthumanpharmacokinetics andstudydrug-druginteractionaswellas thepharmacokineticsinspecialpopulations andinfants.Pharmacokinetic/pharmacodynamicmodelinganditsextension,quantitativesystemspharmacology,canhelp translatepreclinicalfindingstotheclinic.
Thisbookiscomprisedofmanyexcellent chapterswrittenbyexpertsinthefieldthat addresssomeofthechallengeshighlighted inthepreviousparagraph.Thefirstsection focuseson“Techniquesforidentifyingand quantifyingdrugsandmetabolites.” Chapters 1–3 introducethereaderstothelatestadvancesinbioanalysis,inparticularmass spectrometryfortheanalysisofdrugs,their metabolites,andendogenousbiomarkers.In contrastto20yearsago,high-resolution massspectrometryhasnowbecomeroutine andithashadagreatimpactonthestudy ofbiotransformation.Ofcourse,massspectrometryisfrequentlynotsufficienttoidentifythedefinitivestructureofametabolite, andhence Chapter4 focusesonstrategies forgeneratingmetabolitesandcharacterizationviaNMR.Supercriticalfluidchromatographyhasbecomeeasiertointerfaceandit cangreatlyfacilitatechiralseparation;the
lattertopiciscoveredin Chapter5.Thelast chapterinthefirstsection(Chapter6) focusesonacceleratormassspectrometry, apowerfultooltostudyADMEandthe absolutebioavailabilityinhumans.
Thesecondsectionaddresses“Drugmetabolizingenzymes,transportersanddrugdrug interactions.”CytochromeP450-mediated andnon-cytochromeP450-mediatedmetabolismisdiscussedin Chapters7and8. Invitrotoinvivopredictionofdrug-druginteractionisdescribedin Chapter9 while Chapter10 specificallyfocusesontherole oftransportersindrugdispositionand drug-druginteraction,and Chapter11 on theclinicalrelevanceofthesedrug-drug interactions.MakingpredictionsusingPBPK modelingreliesonaccurateknowledgeof physiologicconstantsand,mostrecently, massspectrometryhasbeenusedtodeterminetheabundanceofdrugmetabolizing enzymesandtransportersinvarioustissues. Thisisaddressedin Chapter12.Finally, Chapter13 focusesondisease-druginteractionsmediatedbytherapeuticproteinssuch asinterleukins.
Thethirdsectionfocuseson“Strategyrelatedtodrugmetabolismandsafety.”Metabolitesinsafetytestingcontinuestobea highlyrelevantareaofresearchindrugdiscoveryanddevelopmentanditisaddressed in Chapter14.Acloselookatthe(patent)literatureindicatesthatfindingdrugsthatbalancepotencyandmetabolicstabilitycanstill beproblematic,andthereforemanycompaniesincorporatedeuteriumtoenhance metabolitestabilityandlowerthedose— see Chapter15 fordetails.Thefocusonnovel chemicalspaceandmoremoleculardiversity hasintroducedmorechiralityinmolecules andtheimpactofthatonpharmacology,toxicology,anddrugmetabolismisdescribedin Chapter16.Drug-inducedliverinjuryand newpredictivemodelsforrenalinjuryaredescribedin Chapters17and18,respectively.
Finally, Chapter19 focusesonimmunogenicityasakeycomponentofantibody development.
Thefourthandlastsectionisdedicatedto “Translationalsciences.”Theuseofgeneticallymodifiedrodentsisexploredfurther in Chapter20,while Chapter21 speaksto theuseofCRISPRtoadvanceinvitroADME models.Invitrotoinvivoextrapolationof hepaticandrenalclearanceisdiscussedin Chapter22.Thebreadthofourscienceis nicelyillustratedby Chapter23 whichdescribestheroleofmathematicalmodeling intranslationalsciences.Last,butbyno meansleast, Chapter24 elegantlydefines waystopredictthehumanefficaciousdose usingPK/PDmodeling.
Asisthecasewithmanycompilations,a lotofefforthasgoneintoassemblingan
excellentsetofchaptersthatdescribethe stateoftheartinADMEsciencesasit relatestodrugdiscoveryanddevelopment. Theeffortsbyallauthors,andinparticular theeditorsShuguangMaandSwapan Chowdhury,aregreatlyappreciated.This bookwillbeusedasaresourceformany yearstocome.
CornelisE.C.A.Hop
References [1] B.B.Brodie,Pathwaysofdrugmetabolism,J.Pharm. Pharmacol.8(1)(1956)1–17.
[2] A.Mullard,2019FDAdrugapprovals,Nat.Rev. DrugDiscov.19(2)(2020)79–84.
[3] M.D.Shultz,Twodecadesundertheinfluenceof theruleoffiveandthechangingpropertiesofapprovedoraldrugs,J.Med.Chem.62(4)(2019) 1701–1714.
Preface Some15yearsago,oneofus(SKC)compiledthefirsteditionofthisbookthat coveredthemostup-to-dateinformation previouslyavailableonthestrategies, methods,applications,andimplicationsof scientificdataontheroleofenzymesand transportersinthedispositionofpharmaceuticals.Thebookwasagreatsuccessand waswidelyusedasavaluableresourceby scientistsinbothindustryandacademia. Sincethen,alothaschangedinthefieldof drugmetabolism,includinghowrecent scientificadvancesarebeingutilizedtodiscoveranddevelopsafermedicines.Therefore,ithasbecomeapparentthatanew editionofthebookisrequiredtofullycapturetheseprofoundchanges,whichinvolves theimplementationofnewertechnologiesin thediscoveryanddevelopmentofmedicines totreatawiderangeofmaladies.Withmuch enthusiasmfromthepublisher,wecollaboratedtoassembleacomprehensivetreatise thatwouldcapturehowthelatestscientific findingsarehavingafundamentalimpact ontheutilizationofthesenoveladvances indrugresearch.Thissecondeditionis completelyupdatedandprovidesanoverviewofthelastdecade’snumerousimprovementsinanalyticaltechnologiesforthe detectionandquantificationofdrugs,metabolites,andbiomarkers.Thisneweditiongoes beyondconventionalLC-MSandfeatures all-newchapters,including:howtoevaluate drugabsorption,distribution,metabolism,
andexcretion(ADME),thepotentialforhepaticandrenaltoxicity,immunogenicityof biotherapeutics,andtranslationaltoolsfor predictinghumandosage,safety,andefficacyofsmallmoleculesandbiologics.
Thisbookisorganizedintofoursections: (1)techniquesforidentifyingandquantifyingdrugsandmetabolites,(2)drugmetabolismenzymes,transporters,anddrug-drug interactions,(3)strategiesrelatedtodrug metabolismandsafety,and(4)translationalsciences.Thebookcontains24chapters coveringthemostrecent,novelscientific breakthroughsandhowtheyareutilizedto developmedicinesinthemodernera.Itis oursincerehopethatthismaterialwillserve asanimportanttoolanddeskreferencefor pharmacologists,toxicologists,clinicalscientists,andstudentsinterestedinthefields ofpharmacology,biochemistry,anddrug metabolism.
Finally,wewishtoacknowledgethecontributionsofthemanyscholarswhoparticipatedinandcontributedtothisbookfrom conceptionandpassionintoprint.Wealso wanttoextendourgratitudetothecontributionsoftheeditorialstaffandproduction manageratElsevier,andlastbutnotleast, thefamiliesoftheeditorsfortheirencouragement,love,andsupport.
ShuguangMa SwapanK.Chowdhury
1 Bioanalysisofsmallandlarge moleculedrugs,metabolites,and biomarkersbyLC-MS NaidongWeng,ShefaliPatel,WenyingJian
DMPK,JanssenR&D,SpringHouse,PA,UnitedStates
1Introduction
Bioanalysis,oftenshortenedtoBA,isasubdisciplinewithinpharmaceuticalresearchand development(R&D).Contemporarybioanalysisquantitativelyanalyzesverylowquantity buthighlyvariablelevels(pg/mL-μg/mL)ofdrugcandidates,theirmetabolites,endogenous biomarkers,etc.inextremelycomplicatedbiologicalmatricessuchasplasma,blood,urine, andtissueswhichareharvestedfromdifferenttypesofanimalspecies(rodents,dogs, nonhumanprimates,etc.)andhumans [1].Bioanalysissupportsdiscovery,nonclinical (tox),andclinicalstudies(Fig.1). Fig.1 showstypicalstudiesanintegratedbioanalyticalfunctionwouldsupport.
Bioanalyticaldataareusedforcalculatingpharmacokineticparameterssuchasbioavailability,bioequivalence,drugandmetabolitesexposure,clearance,theirdistributioninto variousbodyorgans,correlationofpharmacokinetics(PK)effectsandpharmacodynamics (PD)changes,etc.Thus,bioanalysisplaysapivotalroleinmovingdrugcandidatesfromearly discoveryallthewaytoregulatoryfilingandpostmarketsurveillanceintheentiredrugdiscoveryanddevelopmentprocess.Intoday’sdynamicdrugdiscoveryanddevelopment environment,bioanalyticalscientistsnotonlyprovidepivotaldatabutalsoactivelyengage inproject/programgo/no-godiscussions,alongwithcolleaguesfromotherfunctionalareas. Whilethemostessentialelementofbioanalysisistouseanalyticalchemistryknowledgeand state-of-the-artinstrumentstoprovidereliableandaccuratemeasurement,knowledgefrom relevantdisciplinessuchasbiotransformation,pharmacokinetics,biology,pharmacology, etc.isinvaluableforensuringappropriateconductofbioanalysis.
1Bioanalysisofsmallandlargemoleculedrugs,metabolites,andbiomarkers
Discovery In vitro
Plasma protein binding
Transporter
Inhibition-induction
Metabolic stability
Plasma-blood distribution
In vivo
Salt form selection
Formulation
Dose range finding
Preclinical Clinical Short term (2wk, 4 wk) TOX
Long term (3mts +) TOX
Reproductive TOX
Carcinoma studies
Micronucleus studies
Animal ADME
Bioavailability (IV/ORAL )
SAD, MAD
Metabolite assessment (MIST)
Food effect
Drug-drug interaction
Comparator study
Human ADME
Population PK
Special population study (renal impaired, pediatric, etc.)
Adaptive design clinical trial
Bioequivalence
Tissue distribution Drug-like?Known liabilities?Superior efficacy?
FIG.1 Exemplarybioanalyticalsupportindrugdiscoveryanddevelopment.TOX,toxicology;SAD,singleascendingdosestudy;MAD,multipleascendingdosestudy;ADME,absorption,distribution,metabolism,andelimination; IV,intravenous.
Inthisbookchapter,wetrytoprovideabriefoverviewofcontemporarybioanalysisusing theLC-MSplatform.Itisanimpossibletasktoprovideadetailedandcomprehensivereview ofLC-MSbioanalysisinabookchapter.Thecasestudiesandliteraturearenodoubtincompleteandbiasedtowardourownexperiencesandpublications.Interestedreadersare referredtotheexcellentbioanalysishandbookbyLietal.foramorecomprehensiveoverview ofthisdiscipline [1].Nevertheless,wehopethereaderscanappreciatethecomplexityand dynamicsofmodernLC-MS-basedbioanalysisforsmallandlargemoleculedrugs,metabolites,andbiomarkers.
2Complexityofcontemporarybioanalysis Bioanalyticalsupportisrequiredforimportantdecision-makingforalltypesofstudies, fromdiscovery(non-GLP),todevelopment(GLP),andtoclinical(GCP)studies.Yetthere aremanyuniqueandcomplicatedattributesofcost,quality,andtimelydeliveryateachof theabovementionedstages(orsubstagewithineachstage).Forbioanalysis,thequality andintegrityofthebioanalyticaldataareultimatelythemostimportantattributes.Theright scientificandcompliancevigormustbeappliedtoeachstudy.Thecurrentregulatorylandscapeforregulatedbioanalysisishighlycomplicated,withguidancefrommultipleregional healthauthorities [2–6].Sinceguidancefromdifferentregionsarenottotallyharmonized,and compoundedbyindividualinterpretationofdifferentinspectors,itisstillquiteachallengeto fullyunderstandandexecutetherightlevelofcompliancethatcanbeacceptableintheglobal filing.Effortsarecurrentlybeingmadetoharmonizetheguidelinesintoonesingleglobal guidelineICH-M10 [7]
Whiletimelydeliveryofbioanalyticaldatatosupportprojectdecisionsisamust-doitemto meettheever-tighteningdrugdiscoveryanddevelopmenttimelines,costisanotherattribute thatshouldnotbeoverlooked.Thecostofbioanalysisactivitiesshouldbecarefullymanaged toensurethatitstayswithinthepredeterminedbudget.Ontheotherside,theapplicationofa
I.Techniquesforidentifyingandquantifyingdrugsandmetabolites
tieredapproach,whichtypicallyconsistsofthreetiersofassayqualification—screeningassay,qualifiedassay,andvalidatedassaywiththeincreasedlevelsofvalidationparameters— canbeusedwithabalanceofscientificvigorandcost [8].TheEuropeanBioanalyticalForum (EBF)recommendsexercisingthisapproachfor“nonregulated”nonclinicalbioanalysisin drugdevelopmentandusing“fit-for-purpose”elementsinmetabolitequantitationfor establishingsafetycoverage(MIST);urinebioanalysis;andtissuebioanalysis [9,10].Of course,theactualimplementationofwhichtiertousedependsoneachindividualstudy. Forexample,forurinebioanalysis,whileaqualifiedassaycouldbeusedformostclinical studiesforunderstandingtheurinaryexcretionofadrugcandidate,validatedassaysshould beappliedifrenalclearanceisthemainrouteofelimination(PKendpoint)and/orthedrug targetactionisatthekidney.
Thereisanexpansionofbioanalysisscopeoverthepastdecades.Intheearlydays, bioanalysisfocusedonsupportingsmallmoleculePKandbioequivalence(BE)fromstandard formulationssuchastabletsandcapsules.Analysisofmetabolitesandbiomarkersrarely occurred.Currently,PKandBEforbothsmallandlargemolecules,aswellasmanyhybrid formsoflargeandsmallmoleculessuchasantibodydrugconjugate(ADC),aresupported bybioanalysis [11,12].Evenforsmallmolecules,advancementinformulationpresentsnew challengesforbioanalysis.Forexample,liposomesarewidelyappliedinthepharmaceutical industryduetotheiruniquecapabilitiessuchasencapsulatingandprotectingthetherapeutic analytesfromdegradation,controllingthereleaserate,facilitatingon-targetdelivery,and reducingtoxicityfordrugs [13,14].Forliposomaldrugproductdevelopment,validated bioanalyticalmethodstodeterminetheconcentrationoftheencapsulatedandnonencapsulated forms(boththeprotein-freeandprotein-bound)oftheactivesubstanceinbiologicalsamples shouldbeemployed.However,establishingsuchbioanalyticalassayscanbequitechallenging duetothepotentialraptureoftheliposomeduringsamplecollection,shipping,storage,and analysis,whichcanartificiallyelevatethenonencapsulatedconcentrations [15,16].
Peptideandproteindrugshaveevolvedinrecentyearsintomainstreamtherapeutics, representingasignificantportionofthepharmaceuticalmarket [17].Peptidesandproteins exhibithighlydiversestructuresandbroadbiologicalactivitiesashormones,neurotransmitters,structuralproteins,andmetabolicmodulatorsandthereforehaveasignificantroleas boththerapeuticsandbiomarkers.Unspecificproteolysisisamajoreliminationpathway forpeptidesandproteinsinsteadoftheoxidativehepaticmetabolismthatistypicalformost smallmoleculedrugs [18].InadditiontothetypicalPKsupport,bioanalysishasbeenactively engagedinnewlydevelopedareassuchasPKPDcorrelation,biomarkerresearchintarget engagement/tissuedistribution,simultaneousquantitationandmetaboliteidentification forsmallmoleculesandbiologics,andantidrugantibody(ADA),etc.,formanyofwhichboth scienceandregulatoryrequirementsarestillevolving.
Historically,bioanalysissupportcanbecategorizedintotwodistinctareas—liquidchromatographyforsmallmolecules,usuallychemicallysynthesized,andligandbindingassay forlargemolecules,suchasthosewhichmonoclonalantibodiestypicallyproducebycell culture.Withthedevelopmentofmoderninstrumentation,especiallymassspectrometers, measurementoflargemoleculesbyliquidchromatographyinconjunctionwithamassspectrometer(LC-MS)hasbecomeareality.ThereisalsoaneedtouseLC-MStoinvestigatethe invivofateofsomeofthenewmodalitiessuchasahalf-lifeextendedpeptideconstructed byconjugatingorfusinganotherwiseshort-livedpeptidewithanantibodyorFctoextensivelyextenditsinvivohalf-lifethroughdecreasedclearanceandincreasedstability [19].
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