Ernst Schering Research Foundation Workshop 59 Appropriate Dose Selection – How to Optimize Clinical Drug Development Ernst Schering Research Foundation Workshop 59 Appropriate Dose Selection – How to Optimize Clinical Drug Development J. Venitz, W. Sittner Editors With 36 Figures 123 SeriesEditors:G.StockandM.Lessl LibraryofCongressControlNumber:2006928310 ISSN 0947-6075 ISBN-10 3-540-27867-2 SpringerBerlinHeidelbergNewYork ISBN-13 978-3-540-27867-2 SpringerBerlinHeidelbergNewYork Thisworkissubjecttocopyright.Allrightsarereserved,whetherthewholeorpartofthe materialisconcerned,specificallytherightsoftranslation,reprinting,reuseofillustrations, recitation,broadcasting,reproductiononmicrofilmsorinanyotherway,andstorageindata banks.Duplicationofthispublicationorpartsthereofispermittedonlyundertheprovisionsof theGermanCopyrightLawofSeptember9,1965,initscurrentversion,andpermissionforuse mustalwaysbeobtainedfromSpringer-Verlag.Violationsareliableforprosecutionunderthe GermanCopyrightLaw. SpringerisapartofSpringerScience+BusinessMedia springer.com ©Springer-VerlagBerlinHeidelberg2007 Theuseofgeneraldescriptivenames,registerednames,trademarks,etc.inthispublicationdoes notemply,evenintheabsenceofaspecificstatemant,thatsuchnamesareexemptfromthe relevantprotectivelawsandregulationsandthereforfreeforgeneraluse.Productliability:The publishercannotguaranteetheaccuracyanyinformationaboutdosageandapplicationcontained inthisbook.Ineveryinduvidualcasetheusermustchecksuchinformationbyconsultingthe relevantliterature. Editor:Dr.UteHeilmann,Heidelberg DeskEditor:WilmaMcHugh,Heidelberg ProductionEditor:MonikaRiepl,Leipzig Coverdesign:WMXDesignGmbH,Heidelberg Typesettingandproduction:LE-TEXJelonek,Schmidt&VöcklerGbR,Leipzig 21/3100/YL–543210 Printedonacid-freepaper Preface Cancerhasbecomeachronicdisease,oftenrequiringlong-term,chronic oncologicaldrugtreatment.Asaresult,theoncologicaltreatmentisex- posedtoalargenumberofpatientswhomaybeonconcurrenttreatments for other health conditions and/or who may suffer from concomitant illnesses,bothofwhichmayaffecttheefficacyandsafetyoftheonco- logicaltreatmentbycontributingtotheincreasedincidenceofadverse eventsand/orlossofefficacy. VI Preface Newer oncological drugs also have become more targeted to the underlyingdiseaseprocess(es),andtheiruseanddosageregimensmay needtobetailoredtoindividualpatients. Therefore,asopposedtothe olderchemotherapeuticdrugs,thesenewagentsareusuallynotdosedto theirmaximaltolerateddose(MTD),andoptimaldoseindividualization hasbecomemoreimportanttoimprovetheirclinicalefficacyandsafety. Atthesametime,theoveralldrugdevelopmentprocesshasbecome more time-consuming and expensive while more potential biological targetsincancerarebeingexplored.Noveldrugcandidatesarescreened inearlyclinicaldrugdevelopment(ECDD),basedontheirclinicalsafety, pharmacokinetic(PK)propertiesandachievementofdesiredbiological effects;drugcandidatessurvivingthisearlyclinicalscreenundergomore rigorousandlarge-scalephaseIIItestingtodemonstratetheirsafetyand efficacyforregulatoryapprovalandclinicaluse. Unfortunately, quite a few of these new oncological agents, both approvedandunderdevelopment,havelessfavorablebiopharmaceuti- calcharacteristics,especiallyforchronicoraladministration,e.g.,poor gastrointestinal solubility and/or permeability and/or extensive drug metabolism, leading to low oral bioavailability and a high degree of variabilityamongpatientsinsystemicdrugexposureandpharmacody- namic(PD)orclinicaldrugresponse.Effectivechroniccancertreatment requiresinformationonintrinsicandextrinsicpatientfactorsimpacting the clinical drug response, e.g., drug–drug interactions (DDIs), phar- macogenetic (PG) differences, etc. The basic sciences provide more, albeit incomplete, knowledge about the fundamental mechanisms of drug disposition, such as drug transporters and metabolic pathways as well as disease biology, such as biological targets, pathophysio- logical pathways, and intermediate markers, i.e., potential biomarkers (BMs). Thisincreasingbodyofknowledgeisonlyslowlytranslatedintothe optimalclinicaluseoftheseagents: • We appreciate the role that patient subpopulations may play in the outcomesofclinicaltrials,basedontheirresponseorlackthereofto drugtreatment. • WearelearningmoreaboutpossibleBMsofdrugresponse,efficacy, andsafety,whichmayassistinoptimaldosefinding. Preface VII • Wemayhavetocarefullyindividualizedosageregimensforindivid- ualpatients. Optimal dose finding requires integration of exposure–response (ER) relationshipsthroughouttheclinicaldrugdevelopment(CDD)process byquantitativemethods.FrontloadingCDDtofailpoordrugcandidates early in the development process has put the burden on early clinical drugdevelopmentto: • Provideearlyproofof(biologicaland/ortherapeutic)concept(POC) fornoveltargets/drugcandidatesinordertomakego/nogodecisions. • Rationally select dosing regimens in phase I and II information to optimize chances ofsuccess in phaseIIIby integrating information across in vitro/in vivo (different species) PK/PD/clinical studies to selectappropriatedosesandBM. • Supportdrugproductlabelinginformationforsafeandeffectiveuse inpostapprovalclinicaluse. Ultimately,theclinicaldevelopmentprocesshastoprovidethefollowing information for the optimal clinical use in order to minimize risk and maximizebenefitofthenewdrugtreatment: 1. Whataretheoddsofachievingdesiredclinicaloutcomes,i.e.,efficacy withouttoxicity? Whichpatientsareathighorlowriskorstandtobenefitthemost?Can these subpopulations be identified a priori? How should the dosage regimenbeindividualizedtominimizeharmandmaximizebenefit? What marker or level of exposure can be monitored during long- term treatment, and how should the dosage regimen be adjusted, if necessary,e.g.,duetoDDI? 2. Whatarethestakesintermsofbenefitorharm? What are the clinical consequences of lack of efficacy and adverse events,giventheseriousnessoftheunderlyingcancerdisease?What areclinicalalternativedosingregimens,drugcombinations,orother treatments? The answers to these questions, based on empiric evidence, theoret- ical considerations (e.g., PK/PD modeling), and clinical judgment are VIII Preface mandatoryprerequisitesforrationaldrugdevelopmentandriskmanage- mentbydrugdevelopersandmanufacturers,regulatoryagencies,health careproviders,andsocietyatlarge. This workshop brought together experts from throughout the world topresentanddiscussthefollowingissues: 1. HowtodemonstratePOC(biological/therapeutic)inECDDandhow todesignpivotalphaseI/IIprograms. 2. HowtoevaluateBMinECCDandthroughoutCDD. 3. HowtoexploreERfordrugresponseandtoxicitythroughoutCDD andhowtodesignoptimaldoserangingstudiesinphasesIandII. 4. How to select an appropriate, i.e., likely to succeed in phase III, dosingregimeninECDDandhowtodefine“optimaldose”. 5. Howtolabel adrugproductforsafeandeffectiveclinical useafter approvalinthemarketplace. Afterexcellentpresentationsandfrankdiscussions,consensusemerged that the current preponderance of empiricism in oncology drug devel- opmentshouldbereplacedbyabettermechanisticunderstandingofthe underlyingdiseasebiologyandtargetalongwiththehumandrugdispo- sitionfortheneweragents,especiallythetargeteddrugs.Co-developing BMwiththedrugcandidateearlycanbeextremelyhelpfulinearlyPOC and better doseselection. This mayalso help tofailearly andcheaply drugcandidateswithalowlikelihoodtosucceedinphaseIII.Inaddition, betterdose–responsetrials(e.g.,randomizedphaseIItrials)areneeded, incorporatingBMand/orclinicalresponse;however,theconceptofthe optimalbiologicallyeffectivedosehasbeenquestionedrecentlydueto our knowledge gap in disease biology. Given the increasing polyphar- macy and co-morbidities in cancer patients, it has become essential to identifyimportantclinicalcovariates,leadingtoPKandPDvariability amongpatients.Finally,optimaldosefindingduringdrugdevelopment is not only able to streamline the drug development and improve drug productlabeling,butalsohelpsavoidpostmarketingchangesinlabeling orevenmarketwithdrawals. WeexpressourgratitudetotheErnstScheringResearchFoundation (ESRF)andDr.MonikaLesslfortheirfinancialandlogisticsupportof this workshop. We also wish to acknowledge the contributions of Dr. BerndMüller,HeadofGlobalPreclinicalDevelopment,ScheringAG,as Preface IX wellFrauYvonneSpiegel,ScheringAG,andFrauKarolaSzivos,ESRF in organizing theevent. We gratefully recognize theinvited presenters and moderators for their lectures, manuscripts, and discussion leads. Finally, we wish to thank the workshop audience for their insightful questionsandcommentsthatmadethisworkshopasuccess. WolfSittner JürgenVenitz Contents 1 ExtrapolationofPreclinicalDataintoClinicalReality– TranslationalScience T.Singer . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2 SmarterCandidateSelection– UtilizingMicrodosinginExploratoryClinicalStudies P.Buchan . . . . . . . . . . . . . . . . . . . . . . . . . . 7 3 TheApplicationsofBiomarkers inEarlyClinicalDrugDevelopment toImproveDecision-MakingProcesses J.Kuhlmann . . . . . . . . . . . . . . . . . . . . . . . . . 29 4 UsingExposure–ResponseandBiomarkers toStreamlineEarlyDrugDevelopment J.Venitz . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 5 ExperienceswithDoseFindinginPatients inEarlyDrugDevelopment: TheUseofBiomarkersinEarlyDecisionMaking S.R.Sultana,S.Marshall,J.Davis,B.H.Littman . . . . . . 65 6 GenotypeandPhenotypeRelationshipinDrugMetabolism I.Roots,G.Laschinski,F.Arjomand-Nahad,J.Kirchheiner, D.Schwarz,J.Brockmöller,I.Cascorbi,T.Gerloff . . . . . 81
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