Drug Discovery Toxicology

From Target Assessment to Translational Biomarkers
 
 
Standards Information Network (Verlag)
  • erschienen am 16. März 2016
  • |
  • 584 Seiten
 
E-Book | PDF mit Adobe DRM | Systemvoraussetzungen
978-1-119-05332-3 (ISBN)
 
As a guide for pharmaceutical professionals to the issues and practices of drug discovery toxicology, this book integrates and reviews the strategy and application of tools and methods at each step of the drug discovery process.
* Guides researchers as to what drug safety experiments are both practical and useful
* Covers a variety of key topics - safety lead optimization, in vitro-in vivo translation, organ toxicology, ADME, animal models, biomarkers, and -omics tools
* Describes what experiments are possible and useful and offers a view into the future, indicating key areas to watch for new predictive methods
* Features contributions from firsthand industry experience, giving readers insight into the strategy and execution of predictive toxicology practices
weitere Ausgaben werden ermittelt
Yvonne Will, PhD, is a Senior Director and the Head of Science and Technology Strategy, Drug Safety Research and Development at Pfizer, Connecticut, USA. She co-edited the book Drug-Induced Mitochondrial Dysfunction, published by Wiley in 2008.
J. Eric McDuffie, PhD, is the Director of the Discovery / Investigative Toxicology and Laboratory Animal Medicine groups at Janssen Research & Development, California, USA.
Andrew J. Olaharski, PhD, is an Associate Director of Toxicology at Agios Pharmaceuticals, Massachusetts, USA.
Brandon D. Jeffy, PhD, is a Senior Principal Scientist in the Exploratory Toxicology division of Nonclinical Development at Celgene Pharmaceuticals, California, USA.
  • Intro
  • TITLE PAGE
  • TABLE OF CONTENTS
  • LIST OF CONTRIBUTORS
  • FOREWORD
  • PART I: INTRODUCTION
  • 1 EMERGING TECHNOLOGIES AND THEIR ROLE IN REGULATORY REVIEW
  • 1.1 INTRODUCTION
  • 1.2 SAFETY ASSESSMENT IN DRUG DEVELOPMENT AND REVIEW
  • 1.3 THE ROLE OF NEW TECHNOLOGIES IN REGULATORY SAFETY ASSESSMENT
  • 1.4 CONCLUSIONS
  • REFERENCES
  • PART II: SAFETY LEAD OPTIMIZATION STRATEGIES
  • 2 SMALL-MOLECULE SAFETY LEAD OPTIMIZATION
  • 2.1 BACKGROUND AND OBJECTIVES OF SAFETY LEAD OPTIMIZATION APPROACHES
  • 2.2 TARGET SAFETY ASSESSMENTS: EVALUATION OF UNDESIRED PHARMACOLOGY AND THERAPEUTIC AREA CONSIDERATIONS
  • 2.3 IMPLEMENTING LEAD OPTIMIZATION STRATEGIES FOR SMALL MOLECULES
  • 2.4 CONCLUSIONS
  • REFERENCES
  • 3 SAFETY ASSESSMENT STRATEGIES AND PREDICTIVE SAFETY OF BIOPHARMACEUTICALS AND ANTIBODY DRUG CONJUGATES
  • 3.1 BACKGROUND AND OBJECTIVES
  • 3.2 TARGET SAFETY ASSESSMENTS: STRATEGIES TO UNDERSTAND TARGET BIOLOGY AND ASSOCIATED LIABILITIES
  • 3.3 STRATEGIC APPROACHES FOR BIOPHARMACEUTICALS AND ADCs
  • 3.4 PREDICTIVE SAFETY TOOLS FOR LARGE MOLECULES
  • 3.5 STRATEGIES FOR SPECIES SELECTION
  • 3.6 STRATEGY FOR DOSE-RANGING STUDIES FOR SAFETY EVALUATION OF BIOPHARMACEUTICALS
  • 3.7 CONCLUSIONS
  • REFERENCES
  • 4 DISCOVERY AND DEVELOPMENT STRATEGIES FOR SMALL INTERFERING RNAs
  • 4.1 BACKGROUND
  • 4.2 TARGET ASSESSMENTS
  • 4.3 siRNA DESIGN AND SCREENING STRATEGIES
  • 4.4 SAFETY LEAD OPTIMIZATION OF siRNA
  • 4.5 INTEGRATION OF LEAD OPTIMIZATION DATA FOR CANDIDATE SELECTION AND DEVELOPMENT
  • 4.6 CONCLUSIONS
  • REFERENCES
  • PART III: BASIS FOR IN VITRO-IN VIVO PK TRANSLATION
  • 5 PHYSICOCHEMISTRY AND THE OFF-TARGET EFFECTS OF DRUG MOLECULES
  • 5.1 LIPOHILICITY, POLAR SURFACE AREA, AND LIPOIDAL PERMEABILITY
  • 5.2 PHYSICOCHEMISTRY AND BASIC ADME PROPERTIES FOR HIGH LIPOIDAL PERMEABILITY DRUGS
  • 5.3 RELATIONSHIP BETWEEN VOLUME OF DISTRIBUTION (Vd) AND TARGET ACCESS FOR PASSIVELY DISTRIBUTED DRUGS
  • 5.4 BASICITY, LIPOPHILICITY, AND VOLUME OF DISTRIBUTION AS A PREDICTOR OF TOXICITY (T): ADDING THE T TO ADMET
  • 5.5 BASICITY AND LIPOPHILICITY AS A PREDICTOR OF TOXICITY (T): SEPARATING THE D FROM T IN ADMET
  • 5.6 LIPOPHILICITY AND PSA AS A PREDICTOR OF TOXICITY (T): ADDING THE T TO ADMET
  • 5.7 METABOLISM AND PHYSICOCHEMICAL PROPERTIES
  • 5.8 CONCENTRATION OF COMPOUNDS BY TRANSPORTERS
  • 5.9 INHIBITION OF EXCRETION PUMPS
  • 5.10 CONCLUSIONS
  • REFERENCES
  • 6 THE NEED FOR HUMAN EXPOSURE PROJECTION IN THE INTERPRETATION OF PRECLINICAL IN VITRO AND IN VIVO ADME TOX DATA
  • 6.1 INTRODUCTION
  • 6.2 METHODOLOGY USED FOR HUMAN PK PROJECTION IN DRUG DISCOVERY
  • 6.3 SUMMARY OF THE TAKE-HOME MESSAGES FROM THE PHARMACEUTICAL RESEARCH AND MANUFACTURERS OF AMERICA CPCDC INITIATIVE ON PREDICTIVE MODELS OF HUMAN PK FROM 2011
  • REFERENCES
  • 7 ADME PROPERTIES LEADING TO TOXICITY
  • 7.1 INTRODUCTION
  • 7.2 THE SCIENCE OF ADME
  • 7.3 THE ADME OPTIMIZATION STRATEGY
  • 7.4 CONCLUSIONS AND FUTURE DIRECTIONS
  • REFERENCES
  • PART IV: PREDICTING ORGAN TOXICITY
  • 8 LIVER
  • 8.1 INTRODUCTION
  • 8.2 DILI MECHANISMS AND SUSCEPTIBILITY
  • 8.3 COMMON MECHANISMS THAT CONTRIBUTE TO DILI
  • 8.4 MODELS SYSTEMS USED TO STUDY DILI
  • 8.5 IN SILICO MODELS
  • 8.6 SYSTEMS PHARMACOLOGY AND DILI
  • 8.7 SUMMARY
  • REFERENCES
  • 9 CARDIAC
  • 9.1 GENERAL INTRODUCTION
  • 9.2 CLASSICAL IN VITRO/EX VIVO ASSESSMENT OF CARDIAC ELECTROPHYSIOLOGIC EFFECTS
  • 9.3 CARDIAC ION CHANNELS AND IN SILICO PREDICTION
  • 9.4 FROM ANIMAL EX VIVO/IN VITRO MODELS TO HUMAN STEM CELL-DERIVED CMs FOR CARDIAC SAFETY TESTING
  • 9.5 IN VIVO TELEMETRY CAPABILITIES AND PRECLINICAL DRUG DEVELOPMENT
  • 9.6 ASSESSMENT OF MYOCARDIAL CONTRACTILITY IN PRECLINICAL MODELS
  • 9.7 ASSESSMENT OF LARGE VERSUS SMALL MOLECULES IN CV SP
  • 9.8 PATIENTS DO NOT NECESSARILY RESPOND TO DRUGS AND DEVICES AS DO GENETICALLY IDENTICAL, YOUNG MATURE, HEALTHY MICE!
  • REFERENCES
  • 10 PREDICTIVE IN VITRO MODELS FOR ASSESSMENT OF NEPHROTOXICITY AND DRUG-DRUG INTERACTIONS IN VITRO
  • 10.1 INTRODUCTION
  • 10.2 BIOLOGICAL PROCESSES AND TOXIC RESPONSES OF THE KIDNEYS THAT ARE NORMALLY MEASURED IN TOXICOLOGY RESEARCH AND DRUG DEVELOPMENT STUDIES
  • 10.3 PRIMARY CULTURES OF hPT CELLS
  • 10.4 TOXICOLOGY STUDIES IN hPT PRIMARY CELL CULTURES
  • 10.5 CRITICAL STUDIES FOR DRUG DISCOVERY IN hPT PRIMARY CELL CULTURES
  • 10.6 SUMMARY AND CONCLUSIONS
  • REFERENCES
  • 11 PREDICTING ORGAN TOXICITY IN VITRO
  • 11.1 INTRODUCTION
  • 11.2 BIOLOGY OF THE HEMATOPOIETIC SYSTEM
  • 11.3 HEMOTOXICITY
  • 11.4 MEASURING HEMOTOXICITY
  • 11.5 THE NEXT GENERATION OF ASSAYS
  • 11.6 PROLIFERATION OR DIFFERENTIATION?
  • 11.7 MEASURING AND PREDICTING HEMOTOXICITY IN VITRO
  • 11.8 DETECTING STEM AND PROGENITOR CELL DOWNSTREAM EVENTS
  • 11.9 BONE MARROW TOXICITY TESTING DURING DRUG DEVELOPMENT
  • 11.10 PARADIGM FOR IN VITRO HEMOTOXICITY TESTING
  • 11.11 PREDICTING STARTING DOSES FOR ANIMAL AND HUMAN CLINICAL TRIALS
  • 11.12 FUTURE TRENDS
  • 11.13 CONCLUSIONS
  • REFERENCES
  • 12 PREDICTING ORGAN TOXICITY IN VITRO
  • 12.1 INTRODUCTION
  • 12.2 OVERVIEW OF DRUG-INDUCED ADVERSE CUTANEOUS REACTIONS
  • 12.3 OVERVIEW OF IN VITRO SKIN MODELS WITH RELEVANCE TO PRECLINICAL DRUG DEVELOPMENT
  • 12.4 SPECIFIC APPLICATIONS OF IN VITRO SKIN MODELS AND PREDICTIVE IN VITRO ASSAYS RELEVANT TO PHARMACEUTICAL DEVELOPMENT
  • 12.5 MECHANISM-BASED CUTANEOUS ADVERSE EFFECTS
  • 12.6 SUMMARY
  • REFERENCES
  • 13 IN VITRO METHODS IN IMMUNOTOXICITY ASSESSMENT
  • 13.1 INTRODUCTION AND PERSPECTIVES ON IN VITRO IMMUNOTOXICITY SCREENING
  • 13.2 OVERVIEW OF THE IMMUNE SYSTEM
  • 13.3 EXAMPLES OF IN VITRO APPROACHES
  • 13.4 CONCLUSIONS
  • REFERENCES
  • 14 STRATEGIES AND ASSAYS FOR MINIMIZING RISK OF OCULAR TOXICITY DURING EARLY DEVELOPMENT OF SYSTEMICALLY ADMINISTERED DRUGS
  • 14.1 INTRODUCTION
  • 14.2 IN SILICO AND IN VITRO TOOLS AND STRATEGIES
  • 14.3 HIGHER-THROUGHPUT IN VIVO TOOLS AND STRATEGIES
  • 14.4 STRATEGIES, GAPS, AND EMERGING TECHNOLOGIES
  • 14.5 SUMMARY
  • REFERENCES
  • 15 PREDICTING ORGAN TOXICITY IN VIVO-CENTRAL NERVOUS SYSTEM
  • 15.1 INTRODUCTION
  • 15.2 MODELS FOR ASSESSMENT OF CNS ADRs
  • 15.3 SEIZURE LIABILITY TESTING
  • 15.4 DRUG ABUSE LIABILITY TESTING
  • 15.5 GENERAL CONCLUSIONS
  • REFERENCES
  • 16 BIOMARKERS, CELL MODELS, AND IN VITRO ASSAYS FOR GASTROINTESTINAL TOXICOLOGY
  • 16.1 INTRODUCTION
  • 16.2 ANATOMIC AND PHYSIOLOGIC CONSIDERATIONS
  • 16.3 GI BIOMARKERS
  • 16.4 CELL MODELS OF THE GI TRACT
  • 16.5 CELL-BASED IN VITRO ASSAYS FOR SCREENING AND MECHANISTIC INVESTIGATIONS TO GI TOXICITY
  • 16.6 SUMMARY/CONCLUSIONS/CHALLENGES
  • REFERENCES
  • 17 PRECLINICAL SAFETY ASSESSMENT OF DRUG CANDIDATE-INDUCED PANCREATIC TOXICITY
  • 17.1 DRUG-INDUCED PANCREATIC TOXICITY
  • 17.2 PRECLINICAL EVALUATION OF PANCREATIC TOXICITY
  • 17.3 PRECLINICAL PANCREATIC TOXICITY ASSESSMENT: IN VIVO
  • 17.4 PANCREATIC BIOMARKERS
  • 17.5 PRECLINICAL PANCREATIC TOXICITY ASSESSMENT: IN VITRO
  • 17.6 SUMMARY AND CONCLUSIONS
  • ACKNOWLEDGMENTS
  • REFERENCES
  • PART V: ADDRESSING THE FALSE NEGATIVE SPACE-INCREASING PREDICTIVITY
  • 18 ANIMAL MODELS OF DISEASE FOR FUTURE TOXICITY PREDICTIONS
  • 18.1 INTRODUCTION
  • 18.2 HEPATIC DISEASE MODELS
  • 18.3 CARDIOVASCULAR DISEASE MODELS
  • 18.4 NERVOUS SYSTEM DISEASE MODELS
  • 18.5 GASTROINTESTINAL INJURY MODELS
  • 18.6 RENAL INJURY MODELS
  • 18.7 RESPIRATORY DISEASE MODELS
  • 18.8 CONCLUSION
  • REFERENCES
  • 19 THE USE OF GENETICALLY MODIFIED ANIMALS IN DISCOVERY TOXICOLOGY
  • 19.1 INTRODUCTION
  • 19.2 LARGE-SCALE GENE TARGETING AND PHENOTYPING EFFORTS
  • 19.3 USE OF GENETICALLY MODIFIED ANIMAL MODELS IN DISCOVERY TOXICOLOGY
  • 19.4 THE USE OF GENETICALLY MODIFIED ANIMALS IN PHARMACOKINETIC AND METABOLISM STUDIES
  • 19.5 CONCLUSIONS
  • REFERENCES
  • 20 MOUSE POPULATION-BASED TOXICOLOGY FOR PERSONALIZED MEDICINE AND IMPROVED SAFETY PREDICTION
  • 20.1 INTRODUCTION
  • 20.2 PHARMACOGENETICS AND POPULATION VARIABILITY
  • 20.3 RODENT POPULATIONS ENABLE A POPULATION-BASED APPROACH TO TOXICOLOGY
  • 20.4 APPLICATIONS FOR PHARMACEUTICAL SAFETY SCIENCE
  • 20.5 STUDY DESIGN CONSIDERATIONS FOR GENOMIC MAPPING
  • 20.6 SUMMARY
  • REFERENCES
  • PART VI: STEM CELLS IN TOXICOLOGY
  • 21 APPLICATION OF PLURIPOTENT STEM CELLS IN DRUG-INDUCED LIVER INJURY SAFETY ASSESSMENT
  • 21.1 THE LIVER, HEPATOCYTES, AND DRUG-INDUCED LIVER INJURY
  • 21.2 CURRENT MODELS OF DILI
  • 21.3 USES OF iPSC HLCs
  • 21.4 CHALLENGES OF USING IPSCs AND NEW DIRECTIONS FOR IMPROVEMENT
  • 21.5 ALTERNATE USES OF HLCs IN TOXICITY ASSESSMENT
  • REFERENCES
  • 22 HUMAN PLURIPOTENT STEM CELL-DERIVED CARDIOMYOCYTES
  • 22.1 INTRODUCTION
  • 22.2 ADVENT OF hPSCs: REPROGRAMMING AND CARDIAC DIFFERENTIATION
  • 22.3 iPSC-BASED DISEASE MODELING AND DRUG TESTING
  • 22.4 TRADITIONAL TARGET-CENTRIC DRUG DISCOVERY PARADIGM
  • 22.5 iPSC-BASED DRUG DISCOVERY PARADIGM
  • 22.6 LIMITATIONS AND CHALLENGES
  • 22.7 CONCLUSIONS AND FUTURE PERSPECTIVE
  • ACKNOWLEDGMENTS
  • REFERENCES
  • 23 STEM CELL-DERIVED RENAL CELLS AND PREDICTIVE RENAL IN VITRO MODELS
  • 23.1 INTRODUCTION
  • 23.2 PROTOCOLS FOR THE DIFFERENTIATION OF PLURIPOTENT STEM CELLS INTO CELLS OF THE RENAL LINEAGE
  • 23.3 RENAL IN VITRO MODELS FOR DRUG SAFETY SCREENING
  • 23.4 ACHIEVEMENTS AND FUTURE DIRECTIONS
  • ACKNOWLEDGMENTS
  • NOTES
  • REFERENCES
  • PART VII: CURRENT STATUS OF PRECLINICAL IN VIVO TOXICITY BIOMARKERS
  • 24 PREDICTIVE CARDIAC HYPERTROPHY BIOMARKERS IN NONCLINICAL STUDIES
  • 24.1 INTRODUCTION TO BIOMARKERS
  • 24.2 CARDIOVASCULAR TOXICITY
  • 24.3 CARDIAC HYPERTROPHY
  • 24.4 DIAGNOSIS OF CARDIAC HYPERTROPHY
  • 24.5 BIOMARKERS OF CARDIAC HYPERTROPHY
  • 24.6 CASE STUDIES
  • 24.7 CONCLUSION
  • REFERENCES
  • 25 VASCULAR INJURY BIOMARKERS
  • 25.1 HISTORICAL CONTEXT OF DRUG-INDUCED VASCULAR INJURY AND DRUG DEVELOPMENT
  • 25.2 CURRENT STATE OF DIVI BIOMARKERS
  • 25.3 CURRENT STATUS AND FUTURE OF IN VITRO SYSTEMS TO INVESTIGATE DIVI
  • 25.4 INCORPORATION OF IN VITRO AND IN VIVO TOOLS IN PRECLINICAL DRUG DEVELOPMENT
  • 25.5 DIVI CASE STUDY
  • REFERENCES
  • 26 NOVEL TRANSLATIONAL BIOMARKERS OF SKELETAL MUSCLE INJURY
  • 26.1 INTRODUCTION
  • 26.2 OVERVIEW OF DRUG-INDUCED SKELETAL MUSCLE INJURY
  • 26.3 NOVEL BIOMARKERS OF DRUG-INDUCED SKELETAL MUSCLE INJURY
  • 26.4 REGULATORY ENDORSEMENT
  • 26.5 GAPS AND FUTURE DIRECTIONS
  • 26.6 CONCLUSIONS
  • REFERENCES
  • 27 TRANSLATIONAL MECHANISTIC BIOMARKERS AND MODELS FOR PREDICTING DRUG-INDUCED LIVER INJURY
  • 27.1 INTRODUCTION
  • 27.2 DRUG-INDUCED TOXICITY AND THE LIVER
  • 27.3 CURRENT STATUS OF BIOMARKERS FOR THE ASSESSMENT OF DILI
  • 27.4 NOVEL INVESTIGATIONAL BIOMARKERS FOR DILI
  • 27.5 IN VITRO MODELS AND THE PREDICTION OF HUMAN DILI
  • 27.6 CONCLUSIONS AND FUTURE PERSPECTIVES
  • REFERENCES
  • PART VIII: KIDNEY INJURY BIOMARKERS
  • 28 ASSESSING AND PREDICTING DRUG-INDUCED KIDNEY INJURY, FUNCTIONAL CHANGE, AND SAFETY IN PRECLINICAL STUDIES IN RATS
  • 28.1 INTRODUCTION
  • 28.2 KIDNEY FUNCTIONAL BIOMARKERS (GLOMERULAR FILTRATION AND TUBULAR REABSORPTION)
  • 28.3 NOVEL KIDNEY TISSUE INJURY BIOMARKERS
  • 28.4 NOVEL BIOMARKERS OF KIDNEY TISSUE STRESS RESPONSE
  • 28.5 APPLICATION OF AN INTEGRATED RAT PLATFORM (AUTOMATED BLOOD SAMPLING AND TELEMETRY, ABST) FOR KIDNEY FUNCTION AND INJURY ASSESSMENT
  • REFERENCES
  • 29 CANINE KIDNEY SAFETY PROTEIN BIOMARKERS
  • 29.1 INTRODUCTION
  • 29.2 NOVEL CANINE RENAL PROTEIN BIOMARKERS
  • 29.3 EVALUATIONS OF NOVEL CANINE RENAL PROTEIN BIOMARKER PERFORMANCE
  • 29.4 CONCLUSION
  • REFERENCES
  • 30 TRADITIONAL KIDNEY SAFETY PROTEIN BIOMARKERS AND NEXT-GENERATION DRUG-INDUCED KIDNEY INJURY BIOMARKERS IN NONHUMAN PRIMATES
  • 30.1 INTRODUCTION
  • 30.2 EVALUATIONS OF NOVEL NHP RENAL PROTEIN BIOMARKER PERFORMANCE
  • 30.3 NEW HORIZONS: URINARY MICRORNAs AND NEPHROTOXICITY IN NHPS
  • REFERENCES
  • 31 RAT KIDNEY MicroRNA ATLAS
  • 31.1 INTRODUCTION
  • 31.2 KEY FINDINGS
  • REFERENCES
  • 32 MicroRNAs AS NEXT-GENERATION KIDNEY TUBULAR INJURY BIOMARKERS IN RATS
  • 32.1 INTRODUCTION
  • 32.2 RAT TUBULAR miRNAs
  • 32.3 CONCLUSIONS
  • REFERENCES
  • 33 MicroRNAs AS NOVEL GLOMERULAR INJURY BIOMARKERS IN RATS
  • 33.1 INTRODUCTION
  • 33.2 RAT GLOMERULAR miRNAs
  • REFERENCES
  • 34 INTEGRATING NOVEL IMAGING TECHNOLOGIES TO INVESTIGATE DRUG-INDUCED KIDNEY TOXICITY
  • 34.1 INTRODUCTION
  • 34.2 OVERVIEWS
  • 34.3 SUMMARY
  • REFERENCES
  • 35 IN VITRO TO IN VIVO RELATIONSHIPS WITH RESPECT TO KIDNEY SAFETY BIOMARKERS
  • 35.1 RENAL CELL LINES AS TOOLS FOR TOXICOLOGICAL INVESTIGATIONS
  • 35.3 CLOSING REMARKS
  • REFERENCES
  • 36 CASE STUDY: FULLY AUTOMATED IMAGE ANALYSIS OF PODOCYTE INJURY BIOMARKER EXPRESSION IN RATS
  • 36.1 INTRODUCTION
  • 36.2 MATERIAL AND METHODS
  • 36.3 RESULTS
  • 36.4 CONCLUSIONS
  • REFERENCES
  • 37 CASE STUDY: NOVEL RENAL BIOMARKERS TRANSLATION TO HUMANS
  • 37.1 INTRODUCTION
  • 37.2 IMPLEMENTATION OF TRANSLATIONAL RENAL BIOMARKERS IN DRUG DEVELOPMENT
  • 37.3 CONCLUSION
  • REFERENCES
  • 38 CASE STUDY: MICRORNAs AS NOVEL KIDNEY INJURY BIOMARKERS IN CANINES
  • 38.1 INTRODUCTION
  • 38.2 MATERIAL AND METHODS
  • 38.3 RESULTS
  • 38.4 CONCLUSIONS
  • REFERENCES
  • 39 NOVEL TESTICULAR INJURY BIOMARKERS
  • 39.1 INTRODUCTION
  • 39.2 THE TESTIS
  • 39.3 POTENTIAL BIOMARKERS FOR TESTICULAR TOXICITY
  • 39.4 CONCLUSIONS
  • REFERENCES
  • PART IX: BEST PRACTICES IN BIOMARKER EVALUATIONS
  • 40 BEST PRACTICES IN PRECLINICAL BIOMARKER SAMPLE COLLECTIONS
  • 40.1 CONSIDERATIONS FOR REDUCING PREANALYTICAL VARIABILITY IN BIOMARKER TESTING
  • 40.2 BIOLOGICAL SAMPLE MATRIX VARIABLES
  • 40.3 COLLECTION VARIABLES
  • 40.4 SAMPLE PROCESSING AND STORAGE VARIABLES
  • REFERENCES
  • 41 BEST PRACTICES IN NOVEL BIOMARKER ASSAY FIT-FOR-PURPOSE TESTING
  • 41.1 INTRODUCTION
  • 41.2 WHY USE A FIT-FOR-PURPOSE ASSAY?
  • 41.3 OVERVIEW OF FIT-FOR-PURPOSE ASSAY METHOD VALIDATIONS
  • 41.4 ASSAY METHOD SUITABILITY IN PRECLINICAL STUDIES
  • 41.5 BEST PRACTICES FOR ANALYTICAL METHODS VALIDATION
  • 41.6 SPECIES- AND GENDER-SPECIFIC REFERENCE RANGES
  • 41.7 ANALYTE STABILITY
  • 41.8 ADDITIONAL METHOD PERFORMANCE EVALUATIONS
  • REFERENCES
  • 42 BEST PRACTICES IN EVALUATING NOVEL BIOMARKER FIT FOR PURPOSE AND TRANSLATABILITY
  • 42.1 INTRODUCTION
  • 42.2 PROTOCOL DEVELOPMENT
  • 42.3 ASSEMBLING AN OPERATIONS TEAM
  • 42.4 TRANSLATABLE BIOMARKER USE
  • 42.5 ASSAY SELECTION
  • 42.6 BIOLOGICAL MATRIX SELECTION
  • 42.7 DOCUMENTATION OF PATIENT FACTORS
  • 42.8 HUMAN SAMPLE COLLECTION PROCEDURES
  • 42.9 CHOICE OF COLLECTION DEVICE
  • 42.10 SCHEDULE OF COLLECTIONS
  • 42.11 HUMAN SAMPLE QUALItY ASSURANCE
  • 42.12 LOGISTICS PLAN
  • 42.13 DATABASE CONSIDERATIONS
  • 42.14 CONCLUSIVE REMARKS
  • REFERENCES
  • 43 BEST PRACTICES IN TRANSLATIONAL BIOMARKER DATA ANALYSIS
  • 43.1 INTRODUCTION
  • 43.2 STATISTICAL CONSIDERATIONS FOR PRECLINICAL STUDIES OF SAFETY BIOMARKERS
  • 43.3 STATISTICAL CONSIDERATIONS FOR EXPLORATORY CLINICAL STUDIES OF TRANSLATIONAL SAFETY BIOMARKERS
  • 43.4 STATISTICAL CONSIDERATIONS FOR CONFIRMATORY CLINICAL STUDIES OF TRANSLATIONAL SAFETY BIOMARKERS
  • 43.5 SUMMARY
  • REFERENCES
  • 44 TRANSLATABLE BIOMARKERS IN DRUG DEVELOPMENT
  • 44.1 SAFETY BIOMARKERS
  • 44.2 QUALIFICATION OF SAFETY BIOMARKERS
  • 44.3 LETTER OF SUPPORT FOR SAFETY BIOMARKERS
  • 44.4 CRITICAL PATH INSTITUTE'S PREDICTIVE SAFETY TESTING CONSORTIUM
  • 44.5 PREDICTIVE SAFETY TESTING CONSORTIUM AND ITS KEY COLLABORATIONS
  • 44.6 ADVANCING THE QUALIFICATION PROCESS AND DEFINING EVIDENTIARY STANDARDS
  • REFERENCES
  • PART X: CONCLUSIONS
  • 45 TOXICOGENOMICS IN DRUG DISCOVERY TOXICOLOGY
  • 45.1 A BRIEF HISTORY OF TOXICOGENOMICS
  • 45.2 TOOLS AND STRATEGIES FOR ANALYZING TOXICOGENOMICS DATA
  • 45.3 DRUG DISCOVERY TOXICOLOGY CASE STUDIES
  • REFERENCES
  • 46 ISSUE INVESTIGATION AND PRACTICES IN DISCOVERY TOXICOLOGY
  • 46.1 INTRODUCTION
  • 46.2 OVERVIEW OF ISSUE INVESTIGATION IN THE DISCOVERY SPACE
  • 46.3 STRATEGIES TO ADDRESS TOXICITIES IN THE DISCOVERY SPACE
  • 46.4 CROSS-FUNCTIONAL COLLABORATIVE MODEL
  • 46.5 CASE-STUDIES OF ISSUE RESOLUTION IN THE DISCOVERY SPACE
  • 46.6 DATA INCLUSION IN REGULATORY FILINGS
  • REFERENCES
  • ABBREVIATIONS
  • CONCLUDING REMARKS
  • INDEX
  • END USER LICENSE AGREEMENT

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