Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays

1404 Pages·2013·25.72 MB·English

by  Dr. Franz J. Hock D.Sc. (auth.)

H. Gerhard Vogel
Jochen Maas
Franz J. Hock
Dieter Mayer
Editors
Drug Discovery
and Evaluation:
Safety and
Pharmacokinetic
Assays
Drug Discovery and Evaluation:
Safety and Pharmacokinetic Assays
H. Gerhard Vogel (cid:129) Jochen Maas
Franz J. Hock (cid:129) Dieter Mayer
Editors
Drug Discovery and
Evaluation: Safety and
Pharmacokinetic Assays
Second Edition
With243Figuresand157Tables
Editors
H.GerhardVogel
Deceased
JochenMaas
SanofiPharmaDeutschlandGmbH
AcompanyoftheSanofi-AventisGroup
IndustrieparkHoechst
FrankfurtamMain,Germany
FranzJ.Hock
Dieburg,Germany
DieterMayer
Idstein,Germany
ISBN978-3-642-25239-6 ISBN978-3-642-25240-2(eBook)
ISBN978-3-642-25241-9(printandelectronicbundle)
DOI10.1007/978-3-642-25240-2
SpringerHeidelbergDordrechtLondonNewYork
LibraryofCongressControlNumber:2012954543
#Springer-VerlagBerlinHeidelberg2006,2013
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In Memory of Hans Gerhard Vogel 1927–2011
Preface to the Second Edition
Both safety and pharmacokinetic aspects are important factors in the Research &
Development of pharmaceuticals: safety pharmacology, toxicology and pharmaco-
kineticsarethecornerstonedisciplinesofpreclinicaldevelopment,butthescopehas
widened both towards Research and towards Development over the last few years.
In this book, all in-silico approaches, in-vitro, ex-vivo, in-vivo animal and clinical
studieshadtobetakenintoconsideration.Thesestudiesareusedtogeneratealotof
data which must be evaluated carefully. It was therefore necessary to include
theconductofstudiesbutalsothetechnologiestogeneratethesedatainatextbook
like this. Since toxicology and safety pharmacology depend directly on exposure,
it was also mandatory to cover PK aspects and technologies. All these aspects
were included in the first edition of Drug Discovery and Evaluation: Safety and
PharmacokineticAssays.
Someofthemethods described inthefirsteditionhavebeenintroducedintothe
scientificcommunityovertheyearsanddecades–forinstancespecificchromatog-
raphy technologies like gas chromatography – and there were no novel tendencies
to be observed between the dates of the first and second editions. These chapters
werenotmodifiedsincealltheinformationincludedcanstillberegardedas"stateof
theart".
Butthereareothertopicswhichhaveshownconsiderabledevelopmentwithmany
newinsightsandtechnologies.Transportersandtheirbiologyarethebestexampleof
theseareas:thesechaptershavebeencompletelymodifiedsincethefirstedition.
A third group of chapters had to consider some new aspects without it being
necessary to modify them completely. These were amended by adding new results
andexperiences.
Andlastbutnotleast,Iwanttothankagainalltheauthorswhocontributeddespite
theirverybusydailylivesinthepharmaceuticalsindustry.Andaspecialthankyouto
Hans Gerhard Vogel who was the Editor-in-Chief of the first edition and all of the
Drug Discovery and Evaluation titles at Springer consisting of Pharmacological
Assays,SafetyandPharmacokineticAssaysandMethodsinClinicalPharmacology.
Gerhard Vogel passed away in 2011. He initiated the second edition of this title.
WithouthimneitherthissecondeditionnoranyoftheothertitlesofDrugDiscovery
andEvaluationwouldeverhavebeencompleted.
Frankfurt,Germany2013 JochenMaas
vii
Preface to the First Edition
Drugdiscoveryandevaluationhasbeenasequentialprocessforalongperiodoftime.
It started with the selection of the most active compound from a series of newly
synthesized compounds with the help of special pharmacological assays. Safety
aspects were considered by testing the selected compound in high doses in tests
directedtoindicationsotherthantheintendedindicationofthenewcompound.These
testswerefollowedbypharmacokineticstudies,whichweremainlyaimedatconfir-
mation of a suitable half-life time and of oral activity. Safety relied on acute and
subacute toxicity studies, which gave information more on organ structure than on
organ function.Toxicological and pharmacokinetic studies were adapted to the
progress of studies in clinical pharmacology and clinical trials. This strategy has
beenchangedduringthelast15yearsforseveralreasons:
Some negative effects on organ function, e.g., ventricular tachy-arrhythmia were
detectedtoolate.Ontheotherhand,negativefindingsinchronictoxicitystudiesin
animalsturnedouttobeirrelevantforhumanbeings.
Newscientificapproaches,e.g.combinatorialchemistry,high-throughputscreening,
in silico models, pharmaco-genomics and pharmaco-proteomics offered new
possibilities.
The success rate in the pharmaceuticals industry and the introduction of new
chemicalentitiestothemarketperyeardroppeddramatically,whereasthedevelop-
menttimefornewcompoundsincreased,sometimesexceedingthepatentprotection.
Thisforcedachangeofstrategy:
• Parallelinsteadofsequentialinvolvementofthevariousdisciplines.
• Theterm“SafetyPharmacology”wascoined.
• An International Conference on Harmonization (ICH) Safety Pharmacolog
workinggroupwasfounded.
• Easilyaccessibleandmostinformativetestsmustbeselected.
Exposureofdrugtothebodybypharmacokineticstudiesonabsorption,distribu-
tion,metabolismandexcretionmustbeinvestigatedatanearlystageofdevelopment
andcancontributetotheselectionofacompoundfordevelopment.
Toxicologyexperiencedmajorimprovementsbytheintroductionofnewmethods,
e.g.,insilicomethods,toxicogenomicsandtoxicoproteomics.
These aspects stimulated our decision topublish this volumeas a counterpart to
“Drug Discovery and Evaluation. Pharmacological Assays” (Second Edition
Springer-Verlag 2002). The current book contains three sections. Dr. Franz Jakob
Hock shares with me the responsibility for the section “Safety Pharmacology”;
Dr.JochenMaastookovertheresponsibilityforthesection“SafetyPharmacokinet-
ics”andProf.Dr.DieterMayerforthesection“SafetyToxicology”.
ix
x PrefacetotheFirstEdition
As with the book on pharmacological assays, this book is intended to aid both
scientistsandstudents.Thereadercanfindmethodsforselectingcandidatesfordrug
development at early stages, such as screening methods based on the stage of
development, or methods up to advanced stages of development and which are
considered necessary for international approval from the scientific and regulatory
pointofview.
Juni2006 H.GerhardVogel
Acknowledgments
"IwanttothankallauthorsofthePK-partfortheirtremendouswork.Itwasoftennot
easytocompletetheirindividualchaptersinadditiontotheirbusydailyactivitiesin
their respective companies. A special thanks goes to Dr. Roland Wesch who
supportedmeinanoptimalwaytocollect,reviewandeditallinformationreceived
fromthedifferentauthors"
JochenMaas
xi
About the Editors
JochenMaas
Jochen Maas is appointed General Manager, Research & Development (R&D)
at Sanofi Deutschland GmbH, as of October 1st, 2010, based in Frankfurt. He is
amemberoftheGlobalR&DManagementBoardandoftheGermanManagement
Board.HewasappointedasheadoftheGermanhubR&Dorganizationin2012.
JochenhashugeexperienceinallphasesoftheR&Dvaluechain.Hestartedhis
career in PK, then he expanded his responsibilities to preclinical Development,
preclinicalandclinicalDevelopmentandResearch&Development.Afterwards,he
was responsible for Global Research & Development in the Diabetes Division and
actedasVicePresidentR&DEuropeatsanofi-aventis.
Jochen also lectures in pharmacokinetics and administering medication as
aprofessoratGießen-FriedbergUniversityofAppliedSciences.
He is a biologist and veterinarian. He has a doctorate in veterinary medicine
including a specification in Radiology. He studied at the Universities of Zurich,
HeidelbergandMunich.AfterjoiningtheGroupin1992asheadofthepharmacoki-
neticslaboratory,heheldvariousR&DmanagementpositionsinGermanyandFrance.
xiii