Comprehensive Guide to Toxicology in Nonclinical Drug Development

Comprehensive Guide to Toxicology in Nonclinical Drug Development
 
 
Academic Press
  • 2. Auflage
  • |
  • erschienen am 3. November 2016
  • |
  • 986 Seiten
 
E-Book | ePUB mit Adobe DRM | Systemvoraussetzungen
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978-0-12-803621-1 (ISBN)
 

A Comprehensive Guide to Toxicology in Nonclinical Drug Development, Second Edition, is a valuable reference designed to provide a complete understanding of all aspects of nonclinical toxicology in the development of small molecules and biologics. This updated edition has been reorganized and expanded to include important topics such as stem cells in nonclinical toxicology, inhalation and dermal toxicology, pitfalls in drug development, biomarkers in toxicology, and more.

Thoroughly updated to reflect the latest scientific advances and with increased coverage of international regulatory guidelines, this second edition is an essential and practical resource for all toxicologists involved in nonclinical testing in industry, academic, and regulatory settings.

  • Provides unique content that is not always covered together in one comprehensive resource, including chapters on stem cells, abuse liability, biomarkers, inhalation toxicology, biostatistics, and more
  • Updated with the latest international guidelines for nonclinical toxicology in both small and large molecules
  • Incorporates practical examples in order to illustrate day-to-day activities and the expectations associated with working in nonclinical toxicology
  • Englisch
  • San Diego
  • |
  • USA
Elsevier Science
  • 19,91 MB
978-0-12-803621-1 (9780128036211)
0128036214 (0128036214)
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  • Front Cover
  • A Comprehensive Guide to Toxicology in Nonclinical Drug Development
  • Dedication
  • A Comprehensive Guide to Toxicology in Nonclinical Drug Development
  • Copyright
  • Contents
  • List of Contributors
  • Foreword
  • 1 - Introduction
  • References
  • I - DRUG DISCOVERY, METABOLISM, AND PHARMACOKINETICS
  • 2 - Critical Aspects of Integrated Nonclinical Drug Development: Concepts, Strategies, and Potential Pitfalls
  • INTRODUCTION
  • TARGET IDENTIFICATION AND VALIDATION
  • PRINCIPAL ASPECTS OF PRECLINICAL TOXICOLOGY TESTING
  • Dose Selection for Toxicity Studies with Small Molecules
  • Dose Selection for Toxicity Studies with?Biopharmaceuticals
  • Species Selection for Small Molecules
  • Species Selection for Biopharmaceuticals
  • PHASE I
  • TGN1412
  • PHASE II
  • Introduction of Salt or Change of Salt Form
  • Impurities
  • PHASE III
  • Clinical Hold
  • PREDICTIVITY OF TOXICOLOGICAL FINDINGS FOR?HUMAN SAFETY
  • Typical Issues and How to Deal with Them: Clinical Intolerance, Liver Toxicity, Nervous System?and Retinal Toxicity, Endocrine D...
  • Cardiotoxicity
  • QT Prolongation
  • Cardiomyopathy
  • The Cardiovascular Safety of Anticancer?Therapies
  • Genotoxicity
  • Positive Ames Test-What Next?
  • Positive In Vitro Mammalian Cell Assay-What Next?
  • Carcinogenicity
  • Positive Results in Rodent Carcinogenicity?Study-What Next?
  • Examples of Rodent Tumors of Questionable Relevance to Humans
  • Target Organ Concordance Between Test?Species and Human
  • Reproductive Toxicity Testing
  • Thalidomide
  • Angiotensin-Converting Enzyme (ACE)?Inhibitors
  • Endothelin Receptor Antagonists
  • Triptanes
  • POSTMARKETING
  • Drug Withdrawal Due to Hepatotoxicity
  • Bromfenac (Duract)
  • Troglitazone (Rezulin)
  • Drug Withdrawal Due to Cardiotoxicity
  • Tegaserod (Zelnorm)
  • Sibutramine (Meridia)
  • CONCLUDING REMARKS
  • References
  • 3 - ADME in Drug Discovery
  • INTRODUCTION
  • Overview of ADME Science
  • ADME in Drug Discovery
  • DRUG ABSORPTION
  • Physicochemical Properties and Permeability
  • Membrane-Bound Drug Transporters
  • ATP Binding Cassette (ABC) Transport Proteins: P-glycoprotein (P-gp, MDR1, ABCB1)
  • BCRP (MXR, ABCG2)
  • BSEP (SPGP, ABCB11)
  • Solute Carrier (SLC) Transport Proteins: Organic Anion Transporting Proteins (OATPs)
  • OTC1
  • SLC Transport Proteins
  • Role of Membrane Transporters on ADME Characteristics of Drugs
  • Transporter Mediated Drug-Drug Interactions: P-glycoprotein
  • Organic Anion (OATs) and Organic Cation Transporters (OCTs)
  • Transporter-Mediated Drug Resistance
  • Methodologies for Evaluating Drug Interactions With Transporters
  • Metabolism in the GIT and Liver: Stability?Testing
  • Stability Testing: Plasma and Microsomal Stability
  • Plasma Stability
  • Microsomal Stability
  • DRUG DISTRIBUTION AND EXCRETION
  • Kinetics of Metabolism in Microsomes, Hepatocyte S9 Fraction, and Hepatocytes
  • Rate of Drug Disappearance in Liver?Microsomes or Hepatocytes [64]
  • In Vivo eADME Disposition and?Balance Studies
  • Drug Distribution Using Molecular Imaging
  • DRUG METABOLISM
  • Biotransformation: Drug Metabolite Profile
  • Role of Mass Spectrometry in Drug Development [61,67-71,80]
  • Feces and Other "Problem" Tissues
  • Drug Disposition Studies Using MS Without Isotopic Labeling
  • Bioactivation
  • Kinetics of Metabolism
  • Drug-Drug Interactions (DDIs)
  • CYP Inhibition and Phenotyping
  • CYP Induction Studies
  • SUMMARY AND TRENDS
  • Use of Preclinical ADME Data
  • Technologies Impacting ADME in Drug Discovery
  • References
  • 4 - Pharmacokinetics and Toxicokinetics
  • INTRODUCTION
  • DRUG ADMINISTRATION AND DELIVERY
  • INTRAVENOUS ADMINISTRATION
  • Clearance
  • Volume of Distribution
  • More Than One Volume Term: Vc, Vss, and Vß
  • Volume of Distribution at Steady State
  • Half-Life
  • Mean Residence Time (MRT)
  • Exposure: Cmax and AUC
  • ABSORPTION AFTER EXTRAVASCULAR DOSING
  • Apparent Half-Life
  • Bioavailability
  • Accumulation
  • CALCULATION OF EXPOSURE-BASED SAFETY MARGINS
  • Predicting Human PK
  • Allometric Scaling of Volume of Distribution
  • Allometric Scaling of Clearance
  • Estimating CL Using a Physiologically Based Approach
  • Prediction of Bioavailability
  • Using Preclinical Data to Set a Safe Human?Starting Dose
  • Pharmacokinetically Guided Dose Extrapolation/Selection
  • The Dose Conversion Approach
  • The Minimum Anticipated Biological?Effect Level
  • Predicting a Human PK Profile
  • PRACTICAL CONSIDERATIONS
  • Formulations
  • Dosing Volumes
  • Fed or Fasted State
  • Sampling Time Points
  • Blood Sampling Limitations
  • Site of Blood Sampling
  • Normalization of Clearance Values to Liver?Blood Flow
  • Evaluation for the Presence of Anti-Drug Antibodies (ADAs)
  • Data Evaluation: Look at a Visual Representation?of the Data (eg, Graphs)
  • Determination of ?z
  • Monitor the "AUC Percent (%) Extrapolated"
  • Examine Outliers
  • Evaluate Potential Changes in TK Parameters on?the Last Study Day Versus Day 1
  • Dose Linearity Versus Dose Proportionality
  • Plasma and Urine Metabolite Identification
  • Determination of Intrinsic Clearance (CLi) by the?Half-Life Method
  • Evaluation of Preclinical In Vitro-In Vivo?Correlations for CL
  • What is a Good Projection of Human Clearance?
  • CONCLUSIONS
  • References
  • II - TOXICOLOGICAL STUDIES AND IND APPLICATION, AND FIRST IN-HUMAN CLINICAL TRIAL
  • 5 - Acute, Subacute, Subchronic, and Chronic General Toxicity Testing for Preclinical Drug Development
  • INTRODUCTION
  • REGULATORY CONSIDERATIONS FOR CONDUCTING?PRECLINICAL TOXICOLOGY STUDIES
  • GENERAL CONSIDERATIONS FOR THE CONDUCT OF?PRECLINICAL TOXICOLOGY STUDIES
  • Preclinical Safety Testing for Phases I-III and Registration Product Label for Marketing Basic Components
  • Selection of Animal Models (Advantages and Disadvantages)
  • Dose Selection and Routes of Administration
  • STUDY TYPES USED IN THE ASSESSMENT OF GENERAL TOXICOLOGY
  • Acute/Dose-Range Finding Toxicity Studies
  • Acute/Repeated-Dose Screening Studies
  • Acute Preclinical Studies for Regulatory Submission
  • REPEATED-DOSE TOXICITY STUDIES
  • Subacute Toxicity Studies (2-4Weeks)
  • Subchronic Toxicity Studies (13Weeks)
  • Chronic Toxicity Studies (6-12Months)
  • SPECIAL CONSIDERATIONS FOR BIOPHARMACEUTICAL?SAFETY EVALUATIONS
  • COMMON PROTOCOL COMPONENTS OF GENERAL TOXICITY ASSESSMENTS IN GLP STUDIES
  • FINAL THOUGHTS
  • References
  • 6 - Genetic Toxicology Testing
  • INTRODUCTION
  • THE CONCEPT OF THRESHOLDS
  • GENETIC TOXICITY TESTING TO SUPPORT CLINICAL TRIALS
  • Guidelines ICHS2(R1) and ICHM3
  • Bacterial Reverse Mutation Assays
  • In Vitro Mammalian Cell Assays
  • In Vitro Chromosome Aberration Test
  • In Vitro Micronucleus Assay
  • Mouse Lymphoma Assay
  • THE SENSITIVITY AND SPECIFICITY OF IN VITRO ASSAYS
  • IN VIVO CORE TESTS
  • In Vivo Micronucleus
  • In Vivo Chromosome Aberration Assay
  • OTHER IN VIVO TESTS FOR GENOTOXICITY
  • DNA Strand-Break Assays: Comet and Alkaline?Elution Assays
  • Transgenic Gene Mutation Test
  • Pig-a Gene Mutation Test
  • In Vivo Unscheduled DNA Synthesis Assay
  • ADDITIONAL TESTS INDICATING GENOTOXICITY
  • In Silico Tools
  • In Vitro Comet and In Vitro Alkaline Elution Assays
  • Syrian Hamster Embryo Cell Transformation Assay
  • Green Screen
  • Yeast Deletion Assay
  • DNA Adducts
  • Toxicogenomics
  • GENETOX TESTING STRATEGY: DISCOVERY THROUGH DEVELOPMENT
  • Early Discovery: Evaluating Chemical Series and Core Structures
  • Lead Optimization
  • Candidate Selection
  • Good Laboratory Practice Studies
  • Exploratory Investigational New Drugs
  • Metabolite Qualification
  • Genotoxic Impurities
  • CONCLUDING REMARKS AND FUTURE DIRECTIONS
  • Acknowledgments
  • References
  • 7 - Contemporary Practices in Core Safety Pharmacology Assessments
  • BACKGROUND AND OVERVIEW
  • SAFETY PHARMACOLOGY AS A REGULATORY SCIENCE
  • TEMPORAL APPLICATION OF CURRENT EXPERIMENTAL PARADIGMS
  • CARDIOVASCULAR SYSTEM AND MODELS OF SAFETY?ASSESSMENT
  • CARDIAC ION CHANNELS AND THE HERG ASSAY
  • IN VIVO CARDIOVASCULAR SAFETY STUDY
  • RESPIRATORY SYSTEM AND MODELS OF SAFETY?ASSESSMENT
  • CENTRAL NERVOUS SYSTEM AND MODELS OF SAFETY ASSESSMENT
  • APPROACHES TO TIER I CNS SAFETY EVALUATION
  • EVALUATING CNS SAFETY
  • References
  • 8 - Preparation of a Preclinical Dossier to Support an Investigational New Drug (IND) Application and First-In-Human Clinical Trial
  • INTRODUCTION
  • Overview of the Nonclinical Toxicology Support?for?Clinical Trials
  • The Common Technical Document (CTD)
  • Preparation of the IND Submission
  • THE DRUG DEVELOPMENT PIPELINE
  • Early Discovery Studies and Their Presentation in the NCO
  • IND/FIH-enabling Studies
  • Advancement of the FIH Candidate-The Core?IND-enabling Studies
  • Safety Pharmacology Section
  • Pharmacokinetics
  • Toxicology
  • Single-Dose Acute Studies
  • Repeat-Dose Studies
  • Genotoxicity Studies
  • Local Tolerance
  • Immunotoxicity
  • Juvenile Animals
  • Summary
  • PRESENTATION OF THE NONCLINICAL PACKAGE
  • The Nonclinical Overview
  • Overview of Nonclinical Testing Strategy
  • Pharmacology
  • Pharmacokinetics
  • Toxicology
  • Relationship of Findings to Pharmacokinetics
  • Target Organs
  • Integrated Overview and Conclusions
  • ESTABLISHING THE CLINICAL SAFETY OF A NEW DRUG CANDIDATE
  • Determine if Proposed Clinical Trial is safe to Proceed
  • Human Equivalent Dose (HED) Calculations
  • Establishing the MRSD or MABEL
  • Safety Factor Considerations
  • SUMMARY AND CONCLUSIONS
  • References
  • 9 - Developmental and Reproductive Toxicology
  • OVERVIEW AND HISTORY OF REPRODUCTIVE?TESTING GUIDELINES
  • Background
  • The Forthcoming Revision of ICH S5 (R2) [6]
  • Early Guidelines
  • ICH Established
  • Reproductive Lifecycle
  • ICH Approach
  • ICH Stages of Development
  • ICH Stage A-Premating to Conception
  • ICH Stage B-Conception to Implantation
  • ICH Stage C-Implantation to Closure of the?Hard Palate
  • ICH Stage D-Closure of the Hard Palate to?the End of Pregnancy
  • ICH Stage E-Birth to Weaning
  • ICH Stage F-Weaning to Sexual Maturity
  • STUDY DESIGNS
  • Study of Fertility and Early Embryonic Development?to Implantation (ICH 4.1.1)
  • Pregnancy and Lactation Labeling
  • Species Selection
  • Common Fertility Protocol Design
  • Dose Selection
  • Number of Animals per Group
  • EVALUATING FERTILITY AND REPRODUCTION
  • EVALUATION OF ESTROUS CYCLING
  • Mating Behavior and Fertilization
  • Preimplantation Loss, Impaired Implantation,?and Uterine Contents
  • Follicle Number and Size
  • Sperm Evaluations
  • HORMONAL REGULATION
  • EMBRYO-FETAL DEVELOPMENT
  • Timing and Exposure
  • Wilson's Principles
  • Study Design Requirements
  • Species
  • Number per Group
  • Treatment Period
  • In-life Observations
  • Maternal Evaluations
  • Fetal Examinations
  • Optional Assessments
  • Terminal Procedures
  • Maternal Examinations
  • Fetal Examinations
  • PRE- AND POSTNATAL DEVELOPMENT STUDIES
  • Selection of Species
  • Treatment Regimen
  • Group Size and Animal Source
  • Dose-Selection Criteria
  • Maternal Endpoints
  • Preweaning Litter Parameters
  • Postweaning Offspring Parameters
  • Behavioral Assessment
  • Immune Function Assessment
  • Data Presentation and Statistical Analysis
  • TOXICOKINETICS
  • DEVELOPMENTAL TOXICITY TESTING OF?BIOPHARMACEUTICALS IN RODENTS AND RABBITS
  • REPRODUCTIVE AND DEVELOPMENTAL ASSESSMENTS IN NONHUMAN PRIMATES
  • Biopharmaceuticals
  • ICH, NHPs, and DART Studies
  • Study of Fertility and Early Embryonic Development?to Implantation (ICH 4.1.1)
  • Embryo-Fetal Development (EFD) Study
  • Enhanced Pre- and Postnatal Development (e-PPND)
  • ALTERNATIVE METHODS USED IN REPRODUCTIVE AND DEVELOPMENTAL TOXICITY TESTING
  • Embryonic Stem-Cell Test (EST)
  • Zebrafish Embryotoxicity Test (ZET)
  • Whole Embryo Culture (WEC)
  • CONCLUDING REMARKS AND FUTURE DIRECTIONS
  • Acknowledgment
  • References
  • 10 - Immunotoxicology Assessment in Drug Development
  • HISTORY AND CURRENT REGULATORY FRAMEWORK FOR IMMUNOTOXICOLOGY TESTING
  • DEVELOPMENTAL IMMUNOTOXICOLOGY
  • Specialized Developmental Considerations
  • Preclinical Developmental Immunotoxicity Testing Strategies
  • EVALUATION OF HUMORAL IMMUNITY
  • EVALUATION OF INNATE IMMUNITY
  • Evaluation of Complement
  • Evaluation of Phagocyte Function
  • Evaluation of Natural Killer Cell Activity
  • Evaluation of Immune-Cell Phenotypes
  • Evaluation of Lymphocyte Proliferation and Cytokine Production
  • Evaluation of Cytokines
  • EVALUATION OF CELL-MEDIATED IMMUNITY
  • INTERPRETATION OF IMMUNOTOXICOLOGY DATA
  • Evaluation of TDAR Data
  • Evaluation of Immunophenotyping Data
  • Evaluation of Proliferation, Natural Killer Cell, and?Cell-Mediated Immunity Data
  • Evaluation of Complement Data
  • Evaluation of Cytokine Data
  • Evaluation of Phagocytosis Data
  • CONCLUDING REMARKS AND FUTURE DIRECTIONS
  • References
  • 11 - Juvenile Testing to Support Clinical Trials in Pediatric Population
  • INTRODUCTION
  • EU AND FDA PEDIATRIC REGULATORY INITIATIVES
  • THE NONCLINICAL SAFETY GUIDELINES
  • STUDY DESIGN CONSIDERATION, SPECIES, AGE,?AND ENDPOINTS
  • TESTING FACILITY
  • APPLICATION OF JUVENILE DATA IN RISK ASSESSMENT
  • References
  • 12 - Preclinical Evaluation of Carcinogenicity Using Standard-Bred and Genetically Engineered Rodent Models
  • INTRODUCTION
  • CHRONIC CARCINOGENICITY BIOASSAYS IN STANDARD-BRED RODENTS
  • Overview
  • Regulatory Compliance
  • Design of 2-Year Carcinogenicity Studies in?Standard-Bred Rodents
  • Experimental Animals
  • Sprague-Dawley Rats
  • F344 (Fischer) Rats
  • Wistar Rats
  • Swiss-Derived Mice (Including ICR and CD-1 Strains)
  • B6C3F1 Mice
  • Experimental Groups
  • Group Size
  • Dose Levels of Test Agent
  • SIX-MONTH CARCINOGENICITY BIOASSAYS IN GENETICALLY ENGINEERED MICE
  • Overview
  • Regulatory Compliance
  • Design of 6-Month Bioassays in Genetically?Engineered Mice
  • Key Differences in the Design of Carcinogenicity Studies?in Standard-Bred and Genetically Engineered Mice
  • Study Duration
  • Group Size
  • Inclusion of a Positive Control Group
  • Genotyping of Study Animals
  • Experimental Animals
  • rasH2 Transgenic Mice
  • Hemizygous p53 Knockout Mice
  • Experimental Groups
  • Group Size
  • Dose Levels of Test Agent
  • GENERAL EXPERIMENTAL PROCEDURES FOR THE CONDUCT OF CARCINOGENICITY BIOASSAYS
  • Laboratory Animal Receipt and Quarantine
  • Animal Age
  • Sentinel Animals
  • Animal Housing
  • Diet and Drinking Water
  • Administration of Test and Control Articles
  • Analytical Chemistry Support
  • In-Life Toxicology Endpoint Evaluations
  • Clinical Observations
  • Mortality/Moribundity Observations
  • Cage-Side Clinical Observations
  • Handheld Clinical and Physical Examinations
  • Body Weight
  • Food Consumption
  • Clinical Pathology
  • Pharmacokinetics
  • Necropsy, Gross Pathology, and Microscopic?Pathology
  • Statistical Analysis
  • References
  • 13 - Current Strategies for Abuse Liability Assessment of New Chemical Entities
  • INTRODUCTION
  • Experimental Protocols
  • Regulatory Guidelines
  • Self-Administration
  • SAMPLE SIZE DETERMINATIONS (POWER)
  • Conditions for Self-Administration of Cocaine
  • Drug Discrimination
  • Drug Dependence Liability
  • DEPENDENCE LIABILITY METHODOLOGIES
  • SAMPLE SIZE DETERMINATIONS FOR DEPENDENCE?LIABILITY STUDIES (POWER)
  • Identification of Discontinuation Syndrome
  • Drug Dependence of the Morphine Type
  • Drug Dependence of the Barbiturate1397059140Alcohol1399746146Type
  • Drug Dependence of the Benzodiazepine Type
  • Drug Dependence of the Cocaine-Amphetamine?Type
  • Drug Dependence of the Khat Type
  • Drug Dependence of the Cannabis?(Marijuana) Type
  • ANCILLARY PARALLEL BEHAVIORAL ASSAYS SENSITIVE?TO WITHDRAWAL
  • References
  • III - CLINICAL PATHOLOGY, HISTOPATHOLOGY, AND BIOMARKERS
  • 14 - Clinical Pathology
  • INTRODUCTION
  • CORE CLINICAL PATHOLOGY TESTING
  • Incorporation of Clinical Pathology Into Multidose?General Toxicology Studies
  • Study Protocol Design
  • Environment and Acclimatization
  • Blood Sampling
  • Blood Sample Handling
  • Urine Collection
  • Analytical Variation and Quality Control
  • Hematology
  • Instrumentation
  • Hematopoiesis
  • Assessment of Hematotoxicity
  • Erythrocytes
  • Reductions in Red Cell Mass
  • Blood Loss (Hemorrhagic Anemia)
  • Nonregenerative Reductions in Red Cell Mass
  • Erythrocytosis
  • Leukocytes
  • Alterations in Leukocyte Counts
  • Neutrophils
  • Eosinophils
  • Basophils
  • Monocytes
  • Lymphocytes
  • Hemostasis
  • Platelets
  • Thrombocytosis
  • Thrombocytopenia
  • Coagulation
  • CYTOLOGICAL EVALUATION OF BONE MARROW
  • EMERGING BIOMARKERS AND APPLICATION WITHIN THE CLINICAL PATHOLOGY LABORATORY
  • CLINICAL PATHOLOGY INDICATORS OF TARGET ORGAN?TOXICITY
  • Assessment of Hepatotoxicity
  • Hepatocellular Enzymes
  • Alanine Aminotransferase
  • Aspartate Aminotransferase
  • Glutamate Dehydrogenase
  • Sorbitol Dehydrogenase
  • Alpha-Glutathione S-Transferase
  • Alkaline Phosphatase
  • Gamma-Glutamyl Transferase
  • Total Bilirubin
  • Total Bile Acids
  • Assessment of Nephrotoxicity
  • Conventional Assessment of Renal Function
  • Urinalysis
  • Emerging Urinary Renal Protein Biomarkers in Preclinical Toxicity Testing
  • Assessment of Cardiotoxicity and Myotoxicity
  • Cardiac Troponins
  • Measurement of Cardiac Troponins
  • High-Sensitivity Cardiac Troponin Assays
  • Other Cardiac Biomarkers
  • Heart-Type Fatty Acid-Binding Protein
  • Natriuretic Peptides
  • Assessment of Myotoxicity
  • Fluid and Electrolyte Balance
  • Endocrine Control of Electrolyte and Fluid Balance
  • Electrolytes
  • Proteins, Lipids, and Carbohydrates
  • Acute-Phase Proteins
  • Lipids
  • Glucose
  • INTERPRETATION OF CLINICAL PATHOLOGY DATA IN?PRECLINICAL SAFETY STUDIES
  • Statistical Analysis, Use of Concurrent?Control, and Historical Reference Range Data
  • Interpretation of Clinical Pathology Data
  • References
  • 15 - Best Practice in Toxicological Pathology
  • INTRODUCTION
  • HISTOPATHOLOGY PROCESSES AND PROCEDURES
  • HISTOPATHOLOGICAL EXAMINATION
  • INTERPRETATION OF PATHOLOGY DATA AND?PATHOLOGY REPORT
  • ADVERSE AND NONADVERSE FINDINGS
  • Adverse Outcome Pathway
  • SPONTANEOUS AND INDUCED HISTOPATHOLOGICAL?LESIONS IN PRECLINICAL STUDIES
  • Principles of General Pathology
  • Spontaneous and Drug-Induced Changes
  • RISK ASSESSMENT
  • References
  • Suggested Further Reading for?Comprehensive Toxicological Pathology
  • 16 - Molecular Pathology: Applications in Nonclinical Drug Development
  • INTRODUCTION
  • IMMUNOHISTOCHEMISTRY
  • Methodology
  • Tissue Fixation
  • Epitope Retrieval
  • Detection Systems
  • Streptavidin/Avidin-Biotin Methods
  • Catalyzed Signal Amplification
  • Polymeric Immunohistochemistry Methods
  • Multiplex Immunostaining Chip Method
  • The Challenges of Laboratory?Immunohistochemistry Practice
  • Immunofluorescence
  • Nonclinical Applications of Immunohistochemistry
  • Analysis of Rodent Carcinogenicity Studies
  • Applications of Immunohistochemistry to Study Mechanisms of Carcinogenesis
  • Applications of Immunohistochemistry in Cancer Drug Development
  • Tissue Microarrays
  • Definition
  • Nonclinical Applications of Microarrays
  • Tissue Cross-Reactivity Studies
  • Regulatory Position
  • Tissues for Tissue Cross-Reactivity Studies
  • The Tissue Cross-Reactivity Immunohistochemistry Configuration
  • Pathology Evaluation of Tissue Cross-Reactivity Studies
  • Nonclinical Implications of Tissue Cross-Reactivity Studies
  • Biodistribution Studies: Nonclinical Applications Based on Immunohistochemistry Configuration
  • Other Methodologies for Tissue-Based Assays
  • Autostainers
  • Histochemistry
  • Laser-Capture Microdissection
  • BIOMARKERS: BEST PRACTICES FOR PATHOLOGY EVALUATION
  • Characterization and Validation of Biomarkers
  • Best Practices for Histopathology Evaluation in?Biomarker Qualification Studies
  • Renal Biomarkers
  • Urinary Biomarkers of Renal Function
  • Blood Biomarker of Renal Function
  • Genomic Biomarker of Renal Function
  • Hepatic Biomarkers
  • Cardiac Biomarkers
  • Skeletal Muscle Biomarkers
  • Vascular Injury Biomarkers
  • Digital Pathology Imaging
  • Imaging in Nonclinical Development
  • Good Laboratory Practice Validation and Regulatory Considerations
  • Image Storage and Retrieval
  • Whole-Slide Image Analysis
  • Computer-Aided Diagnosis
  • Histochemical Measurements
  • Pattern Analysis: Skeletonization
  • Stereology in Image Analysis
  • TOXICOGENOMICS
  • Considerations for the Design of Nonclinical Toxicogenomics Studies
  • Tissue Collection
  • RNA Labeling and Hybridization
  • RNAScope
  • Toxicogenomics Data Analysis Workflow
  • Pathway Analysis
  • Regulatory Aspects of Toxicogenomics Submission
  • MICRORNAS
  • The Biology of MicroRNAs
  • MicroRNAs in Mechanistic Toxicity
  • MicroRNAs as Biomarkers of Organ-Specific Toxicity
  • CONCLUSION
  • References
  • 17 - Biomarkers in Nonclinical Drug Development
  • BIOMARKERS IN NONCLINICAL SAFETY ASSESSMENT
  • BIOMARKER VALIDATION, QUALIFICATION, AND APPLICATION IN NONCLINICAL STUDIES
  • Biomarker Qualification
  • Biomarker Assay Kits
  • Fit-for-Purpose (Analytical) Validation
  • Biomarker Application in Nonclinical Studies
  • Lab-to-Lab and Method-to-Method Diversity
  • BIOMARKERS OF LIVER INJURY
  • Traditional Biomarkers
  • Biomarkers of Hepatocellular Injury
  • Alanine Transaminase
  • Aspartate Transaminase
  • Glutamate Dehydrogenase
  • Sorbitol Dehydrogenase
  • Total Bile Acids
  • BIOMARKERS OF HEPATOBILIARY INJURY
  • Alkaline Phosphatase
  • Total Bilirubin
  • ?-Glutamyl Transferase and Other Hepatobiliary Markers
  • Emerging Biomarkers
  • Glutamate Dehydrogenase
  • Malate Dehydrogenase
  • Paraoxonase-1
  • Purine Nucleoside Phosphorylase
  • Other Emerging Biomarkers of Liver Injury
  • RENAL INJURY BIOMARKERS
  • Tubular Injury Biomarkers
  • Kidney Injury Molecule-1?(Kim-1/TIM-1/HAVCR-1)
  • Neutrophil Gelatinase-Associated Lipocalin or Lipocalin-2
  • Clusterin
  • Cystatin C
  • Enzymuria
  • Glomerular Injury Biomarkers
  • Total Protein, Albumin, and Microglobulins
  • Future Directions
  • CARDIAC AND SKELETAL MUSCLE INJURY BIOMARKERS
  • Biomarkers of Cardiac Structural Injury and Necrosis
  • Biomarkers of Cardiac Functional Alterations
  • Biomarkers of Skeletal Muscle Injury
  • VASCULAR INJURY BIOMARKERS
  • BIOMARKERS OF THE IMMUNE SYSTEM
  • Indicators of Immunosuppression
  • Hematology and Clinical Chemistry
  • Increased Incidence of Tumors
  • Increased Incidence of Infections
  • Histopathology and Lymphoid Organ Weight
  • Immune Function Studies
  • Primary Antibody Assays
  • Natural Killer Cell Activity
  • Macrophage Function
  • Indicators of Adverse Immunostimulation
  • Acute-Phase Proteins
  • Cytokine Evaluation
  • Indicators of Hypersensitivity
  • Indicators of Immunogenicity
  • Indicators of Autoimmunity
  • Biomarkers of Toxicity in the Central Nervous System
  • Biomarkers of Toxicity in the Reproductive System
  • CONCLUSION
  • References
  • IV - BIOSTATISTICS, REGULATORY TOXICOLOGY, AND ROLE OF STUDY DIRECTORS
  • 18 - Biostatistics for Toxicologists
  • INTRODUCTION
  • Study Design
  • BASIC STATISTICAL CONCEPTS
  • Estimation
  • Significance Testing
  • Testing Philosophies
  • Zero-Dose Comparisons
  • Dose-Response Trend Testing
  • Parametric Versus Nonparametric
  • Data Characteristics
  • Count Data
  • CASE STUDIES
  • Case Study-General Toxicology?Example
  • Case Study-Developmental and?Reproductive Toxicology
  • F1: Postnatally
  • Case Study-Carcinogenicity Studies
  • Mortality
  • Tumor Data
  • Case Study-Endocrine Study?(Female Pubertal Study)
  • DISCUSSION
  • References
  • 19 - Regulatory Toxicology
  • INTRODUCTION
  • HISTORY OF REGULATIONS: WHY DO WE NEED THEM?
  • Brief Selective History of Drug Events Leading to Regulations and Toxicology Guideline Development
  • Brief Selective History of Food Events Leading to Regulations and Toxicology Guideline Development
  • Misbranding and Deception Not Limited to Foods
  • Human Tragedies Spark the Need for Tougher Food?and Drug Regulations
  • Diphtheria Antitoxin
  • Diethylene Glycol (Elixir Sulfanilamide)
  • Thalidomide
  • PREVENTING DRUG DISASTERS FROM RECURRING TODAY:?LAWS AND REGULATIONS
  • Lawmakers, Regulators, and Scientists
  • Additional Food and Drug Regulations
  • What Actions Need To Be Implemented to Address?the FD&C Requirements?
  • TRANSLATING REGULATIONS INTO APPROPRIATE SCIENTIFIC DATA-GUIDELINES
  • General Steps in Preclinical Drug Development
  • Guidelines and the Need for Harmonization-Origin?of ICH
  • DEVELOPING THE NONCLINICAL TOXICOLOGY PROGRAM
  • Begin With the Regulatory End Product in Mind
  • ICH Harmonized (and Other) Nonclinical?Toxicology Guidelines
  • Safety Pharmacology Studies
  • Acute Toxicity
  • Repeat-Dose Toxicity
  • Genotoxicity
  • Carcinogenicity
  • Reproductive and Developmental Toxicity
  • Studies in Juvenile Animals
  • Oncology Therapeutics
  • Biotechnology: ICH S6(R1) Updates
  • Vaccines
  • TRANSLATING NONCLINICAL DATA INTO CLINICALLY?USEFUL INFORMATION-DRUG LABELS
  • THE OPPOSITE END OF THE SPECTRUM-HOMEOPATHY
  • ADVANCES IN SCIENCE: IMPACT ON REGULATORY?TOXICOLOGY
  • HOW MUCH PROGRESS HAVE WE MADE?
  • CONCLUSIONS
  • References
  • 20 - Role of Study Director and Study Monitor in Drug Development Safety Studies
  • INTRODUCTION
  • BACKGROUND
  • STUDY DIRECTORS
  • Description
  • Study Conduct
  • Scheduling
  • Additional Considerations
  • STUDY MONITORS
  • Description
  • Reasons for Using a Monitor
  • Selecting a Monitor
  • Considerations While Monitoring
  • STUDY DIRECTOR CHECKLIST
  • STUDY MONITOR CHECKLIST
  • BRINGING IN EXPERTS
  • REGULATIONS
  • CONCLUSIONS
  • References
  • V - SPECIALTY ROUTE OF ADMINISTRATION
  • 21 - Infusion Toxicology and Techniques
  • INTRODUCTION
  • PRECLINICAL INFUSION MODELS
  • REGULATORY GUIDELINES
  • CHOOSING THE APPROPRIATE INFUSION MODEL
  • INFUSION BEST PRACTICES
  • Surgical Models
  • Training
  • Infusion Methodology
  • Limitations and Advantages of the Infusion Model
  • Nonsurgical Models
  • Methods of Restraint and Infusion Techniques
  • Challenges/Advantages
  • INFUSION TECHNIQUES
  • Surgical Model in the Rat
  • Premedication and Anesthesia
  • Presurgical Preparation
  • Surgical Procedure
  • Maintenance
  • Recovery Procedures
  • Caging
  • Infusion System Care
  • Nonsurgical Model in the Rat
  • Methods of Restraint and Acclimation
  • Peripheral Vascular Access
  • Caging
  • Infusion System Evaluation and Troubleshooting
  • Surgical Model in Large Animals
  • Preparation
  • Premedication and Anesthesia
  • Presurgical Preparation
  • Surgical Procedure
  • Maintenance
  • Recovery Procedures
  • Caging
  • Infusion System Evaluation and Troubleshooting
  • Nonsurgical Models
  • Methods of Restraint and Acclimation
  • Methods of Vascular Access
  • Caging
  • Infusion System Evaluation and Troubleshooting
  • EQUIPMENT
  • Surgical Models
  • Surgical Facilities
  • Catheters/Vascular Access Ports
  • External Infusion Equipment for Rats
  • External Infusion Equipment for Large Animals
  • Infusion Pumps
  • BACKGROUND DATA - RESULTANT PATHOLOGIES
  • Surgical Models
  • Complications Associated With the Surgical?Process
  • Issues Associated With Study Design
  • In-Life Changes Associated With the Model
  • Pathology
  • Clinical Pathology
  • Histopathology
  • Common Pathological Findings Related to Intravascular Infusion Procedures in Laboratory Animals When test materials are administ...
  • Necropsy Techniques and Tissue Sampling Successful interpretation of pathological findings in infusion studies is only possible ...
  • Macroscopic and Microscopic Pathology
  • During the in-life portion of the study and during the necropsy, external lesions can occur in the skin associated with the jack...
  • Arteries and veins are generally composed of three layers: an inner layer adjacent to the lumen called the tunica intima, a midd...
  • Catheterized animals on infusion studies can develop systemic lesions, which are often sequelae to the morphological changes des...
  • Organ Weight Changes As might be expected from the macroscopic and microscopic findings described previously, organ weight chang...
  • Species Differences As discussed previously, the range of tissue responses to catheterization and infusion procedures are genera...
  • CONCLUDING REMARKS
  • References
  • 22 - Photosafety Assessment
  • INTRODUCTION
  • REGULATORY STATUS
  • PHOTOSAFETY EVALUATION STRATEGY
  • LIGHT DOSIMETRY
  • LIGHT SOURCES
  • SPECTRAL ABSORPTION
  • REACTIVE OXYGEN SPECIES ASSAY
  • IN VITRO 3T3 NEUTRAL RED UPTAKE?PHOTOTOXICITY TEST
  • RECONSTRUCTED SKIN EPIDERMIS SYSTEMS
  • IN VITRO PHOTOGENOTOXICITY
  • GENERAL IN VIVO TECHNIQUES
  • EVALUATION OF IN VIVO PHOTOTOXIC RESPONSES
  • THE MOUSE
  • THE GUINEA PIG
  • THE RAT
  • THE RABBIT
  • THE PIG
  • Photocarcinogenesis
  • References
  • VI - NONCLINICAL DEVELOPMENT OF MONOCLONAL ANTIBODIES, STEM CELLS, ONCOGENIC AND NON-ONCOGENIC DRUGS, OLIGONUCLEOTIDES, AND VACCINES
  • 23 - Preclinical Development of Monoclonal Antibodies
  • INTRODUCTION
  • HISTORY OF ANTIBODY THERAPEUTICS: THE DISCOVERY OF SERUM THERAPY
  • ANTIBODY STRUCTURE AND FUNCTION
  • The Evolution of Therapeutic Monoclonal Antibodies
  • Mouse mAbs
  • Chimeric and Humanized mAbs
  • Fully Human mAbs Using Phage Display or Transgenic Mice
  • Next-Generation Antibody Therapeutics
  • NOMENCLATURE OF MONOCLONAL ANTIBODIES
  • PRECLINICAL DEVELOPMENT OF MONOCLONAL ANTIBODIES
  • The Fate of Monoclonal Antibodies in the Body
  • Pharmacokinetics, Toxicokinetics, and?Pharmacodynamics of Monoclonal Antibody Therapeutics
  • Tissue Cross-Reactivity Studies
  • Nonclinical Safety Evaluation
  • Animal Care and Use
  • Good Laboratory Practice
  • Species Selection for Nonclinical Testing
  • NONCLINICAL SAFETY EVALUATION/TOXICOLOGY PLANS TO SUPPORT THE FIRST-IN-HUMAN STUDY
  • DOSE SELECTION FOR THE FIH STUDY
  • REPEAT-DOSE TOXICOLOGY STUDIES BEYOND FIH
  • IMMUNOGENICITY OF MONOCLONAL ANTIBODIES
  • IMMUNOTOXICITY
  • REPRODUCTIVE AND DEVELOPMENTAL TOXICITY?EVALUATION
  • Fertility
  • Embryo-Fetal Development
  • Pre-/Postnatal Development Studies
  • CARCINOGENICITY
  • DRUG INTERACTIONS
  • PARTNERSHIP IN MAB DEVELOPMENT
  • SUMMARY
  • References
  • 24 - Nonclinical Safety Assessment of Cell-Based Therapies
  • INTRODUCTION
  • CT SOURCES
  • CT CHARACTERIZATION
  • REGULATORY FRAMEWORK FOR NONCLINICAL ASSESSMENT?OF CT
  • PRECLINICAL STUDY OBJECTIVES
  • PRECLINICAL STUDY DESIGN
  • Animal Models
  • Proof-of-Concept Studies
  • Animal Models of Disease in CT
  • 6-Hydroxydopamine
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Animal Species
  • Immune-Compromised or Immune-Suppressed?CT Models
  • CONSIDERATIONS FOR DOSE AND ROUTE OF?ADMINISTRATION IN CT TESTING
  • FATE OF CT POSTADMINISTRATION (BIODISTRIBUTION)
  • SAFETY CONCERNS ASSOCIATED WITH CT
  • Route-Related Safety Concerns
  • Immunogenicity-Related Safety Concerns
  • Proliferation-Related Safety Concerns
  • References
  • 25 - Preclinical Development of Nononcogenic Drugs (Small and Large Molecules)
  • INTRODUCTION
  • PRECLINICAL DEVELOPMENT OF SMALL MOLECULES
  • Pharmacology Studies
  • Pharmacology Screening
  • Pharmacodynamics
  • Safety Pharmacology
  • Cardiovascular System
  • Central Nervous System
  • Respiratory System
  • PHARMACOKINETICS AND TOXICOKINETICS
  • Absorption
  • Distribution
  • Metabolism
  • Elimination
  • TOXICITY STUDIES
  • Acute (Single-Dose) Toxicity Studies
  • Repeated-Dose Toxicity Studies
  • Subacute Toxicity Studies
  • Subchronic Toxicity Studies
  • Chronic Toxicity Studies
  • Genotoxicity Studies
  • Carcinogenicity Studies
  • Reproduction Toxicity Studies
  • SAFETY EVALUATION OF IMPURITIES AND DEGRADANTS IN?NEW DRUG PRODUCTS
  • CONSIDERATIONS FOR THE CONDUCT OF JUVENILE ANIMAL TOXICITY STUDIES
  • SPECIAL TOXICOLOGY STUDIES
  • Immunotoxicity Studies
  • Photosafety Testing
  • Preclinical Drug Abuse Liability Assessment
  • Approaches and Methods for Abuse Potential Assessments
  • Preclinical Screening
  • Local Tolerance Studies
  • PRECLINICAL DEVELOPMENT OF BIOTECHNOLOGY-DERIVED PHARMACEUTICALS (LARGE MOLECULES)
  • PRECLINICAL SAFETY TESTING OF BIOTECHNOLOGY-DERIVED PHARMACEUTICALS
  • Pharmacodynamics (Biological Activity)
  • Safety Pharmacology Studies
  • Pharmacokinetics and Toxicokinetics
  • Toxicology Assessment
  • Selection of a Relevant Animal Species
  • Toxicology Studies
  • Single-Dose Toxicity Studies
  • Repeated-Dose Toxicity Studies
  • Immunogenicity
  • Immunotoxicity Studies
  • Developmental and Reproductive Toxicity Studies
  • Genotoxicity Studies
  • Carcinogenicity Studies
  • Local Tolerance Studies
  • Comparability Studies
  • References
  • 26 - Preclinical Development of Oncology Drugs
  • INTRODUCTION
  • CYTOTOXIC VERSUS TARGETED DRUGS
  • CANCER IMMUNOTHERAPY
  • IMMUNE CHECKPOINT INHIBITORS
  • THERAPEUTIC ANTIBODIES
  • IMMUNE-CELL THERAPY
  • OTHER IMMUNOTHERAPIES
  • PHARMACOLOGY EVALUATION
  • Overview
  • In Vitro Models
  • In Vitro National Cancer Institute Screening Model
  • Hollow-Fiber Assay
  • Assay Development for Molecularly?Targeted Therapies
  • In Vivo Models
  • TRANSLATIONAL MEDICINE
  • Biomarkers
  • PHARMACOKINETIC AND PHARMACODYNAMIC?MODELING
  • TOXICOLOGY EVALUATION
  • ICH S9
  • Investigational New Drug Application?and New Drug Application-Enabling?Toxicology Program
  • First-in-Human Dose Selection
  • DRUG METABOLISM AND PHARMACOKINETICS
  • Pharmacokinetics
  • Absorption
  • Distribution
  • Metabolism
  • Drug-Drug Interaction Studies
  • Excretion
  • OTHER CONSIDERATIONS: CHANGES IN ROUTE OR?FORMULATION
  • References
  • 27 - Preclinical Toxicology of Vaccines1
  • INTRODUCTION TO VACCINES/ADJUVANTS FOR THE PREVENTION OF INFECTIOUS DISEASES
  • SPECIAL TOPICS
  • Adjuvants
  • Aluminum Adjuvants (Salts)
  • TOXICITIES ASSOCIATED WITH VACCINES
  • TOXICOLOGY STUDIES FOR VACCINES (ADJUVANTS)
  • Types of Study and Their Endpoints
  • Single- and/or Repeat-Dose Toxicology Studies
  • Test and Control Article Characterization (21 CFR Part 58.105 [58])
  • Stability of Test and Control Articles (21 CFR Part 58.105 [58])
  • Reproductive and Developmental Toxicology Studies
  • Category A
  • Category B
  • Category C
  • Category D
  • Category X
  • Mutagenicity Studies
  • Carcinogenicity Studies
  • Safety Pharmacology Studies
  • Other Toxicity Studies
  • ANIMAL MODELS FOR VACCINE RESEARCH
  • Influenza Vaccines and the Selection of the Appropriate Animal Model
  • Mice, Cotton Rats and Guinea Pigs
  • Ferrets
  • Pigs and Cats
  • Monkeys
  • The Selection of Animal Models for Other Vaccines
  • ROUTES OF VACCINE ADMINISTRATION
  • Intranasal Vaccines
  • Alternative Routes
  • Vaccine Injection Versus Intranasal Administration (Live Attenuated Vaccines Versus Killed Vaccines) [200-202]
  • PRODUCT CHARACTERIZATION
  • PEDIATRIC DRUG DEVELOPMENT (PRECLINICAL SAFETY EVALUATIONS)
  • References
  • 28 - Overview of the Nonclinical Development Strategies and Class-Effects of Oligonucleotide-Based Therapeutics
  • INTRODUCTION
  • REVIEW OF PHARMACOLOGICAL CLASSES OF ONTS
  • Antisense Mechanism of Action Mediated by RNase H
  • Antisense Mechanism of Action Mediated by RNA Interference
  • Pharmacology Mediated by Aptamer Interactions With Proteins
  • Overview of Common Chemical Structure Activity Relationships and Pharmacokinetic Properties
  • GENERAL STRATEGY FOR TOXICOLOGY TESTING OF ONTS
  • Regulatory Considerations
  • Selection of Species and Study Design of General Toxicity Studies
  • Safety Pharmacology, Genetic and Special?Toxicity Studies
  • Safety Pharmacology Assessment
  • Immunotoxicology Testing
  • Genetic Toxicity Testing
  • Reproductive Toxicity and Carcinogenicity Testing
  • DISCOVERY TOXICOLOGY OF ONTS
  • Homology/Hybridization-Dependent Off-Target Effects
  • In Vivo Screening-Toleration Studies in Animals
  • NONSPECIFIC CLASS EFFECTS OF ONTS
  • Inhibition of Clotting Time
  • Complement Activation
  • Proinflammatory Effects
  • Tissue and Cellular Accumulation
  • Translation of Key Preclinical Safety Findings?to Humans
  • Safety Implications for Formulated ONTs
  • EXPANDING PROSPECTS FOR ONTS
  • References
  • VII - SAFETY EVALUATION OF OCULAR DRUGS, BOTANICAL PRODUCTS, AND MEDICINAL DEVICES
  • 29 - Safety Evaluation of Ocular Drugs
  • INTRODUCTION
  • PHARMACOKINETICS AND DRUG DISPOSITION IN THE EYE
  • Ocular Pharmacokinetic Profiling
  • Topical Ophthalmic
  • Subconjunctival
  • Intravitreal and Intracameral
  • Drug Metabolism and Transporters
  • Melanin Binding
  • Study Considerations
  • PHARMACOKINETIC CONSIDERATIONS FOR LARGE MOLECULES
  • Determination of Free Drug and Target-Bound Drug Complex
  • Bioanalytical Assay Development
  • Regulatory Considerations in Ocular Safety Assessment
  • PRACTICAL CONSIDERATIONS IN ASSESSING OCULAR SAFETY
  • Study Objective
  • Test Formulation
  • Test Species
  • Route of Administration
  • Study Endpoints
  • Toxicokinetics and Exposure Assessment
  • TECHNIQUES FOR IN-LIFE OCULAR EVALUATION
  • Standard Ocular Examination Procedures
  • Specialized Ocular Examination Techniques
  • Histopathology
  • Tissue Collection
  • Preservation
  • Trimming and Embedding
  • Ocular Globe
  • Extraocular Tissues
  • Sectioning
  • For Standard (Sagittal) Ocular Sectioning
  • For Extraocular Tissues Sectioning
  • EXAMPLES OF ADVERSE EFFECTS IN THE EYE
  • Ocular Surface
  • Anterior Chamber
  • Lens
  • Fundus
  • Translation of Nonclinical Findings
  • OCULAR IMMUNOLOGY: SPECIAL CONSIDERATIONS?FOR BIOLOGIC THERAPEUTICS AND UNDERSTANDING?PRECLINICAL FINDINGS
  • Ocular Immunology
  • Immungenicity Considerations
  • General Considerations
  • Ocular Route of Administration and Caution Regarding Dose Response
  • Species Selection
  • Rodents
  • Nonrodents
  • Translation of Immunogenicity From Animals to?Humans
  • OCULAR IMMUNOPATHOLOGY
  • Innate Immune Responses
  • Adaptive Immune Responses
  • Inflammatory Outcomes Associated With Devices and Implants
  • STRUCTURE AND FUNCTION OF THE EYE
  • Ocular Blood Supply and Drainage
  • Anterior Segment
  • Cornea
  • Conjunctiva
  • Iridocorneal Angle
  • Aqueous Humor Outflow
  • Ciliary Body
  • Iris
  • Lens
  • Back of the Eye and Posterior Segment
  • Ocular Functional Neuroanatomy
  • Retinal Pigment Epithelium
  • Sensory and Neuronal Retina
  • Photoreceptor Segments
  • External Limiting Membrane
  • Outer Nuclear Layer
  • Outer Plexiform Layer
  • Inner Nuclear Layer
  • Inner Plexiform Layer
  • Ganglion Cell Layer
  • Nerve Fiber Layer
  • Internal Limiting Lamina (Membrane)
  • Optic Nerve
  • Sclera
  • Vitreous
  • INTEGRATED ASSESSMENT OF OCULAR TOXICITY
  • References
  • 30 - Nonclinical Safety Assessment of Botanical Products
  • INTRODUCTION OF BOTANICAL PRODUCTS
  • DIETARY SUPPLEMENTS
  • BOTANICAL DRUG PRODUCTS
  • CHEMISTRY, MANUFACTURING, AND CONTROLS INFORMATION FOR BOTANICAL DRUGS
  • QUALITY CONTROL FOR BOTANICAL PRODUCTS
  • SAFETY PACKAGE FOR INVESTIGATIONAL NEW DRUG (IND) AND NEW DRUG APPLICATION (NDA) OF BOTANICAL DRUGS
  • BOTANICAL PRODUCTS WITHOUT SAFETY CONCERNS
  • BOTANICAL DRUGS WITH SAFETY CONCERNS
  • SAFETY PACKAGE TO SUPPORT PHASE III CLINICAL STUDIES AND NDA OF BOTANICAL DRUGS
  • GENERAL TOXICITY STUDIES
  • GENETIC TOXICITY
  • PHARMACOKINETICS AND TOXICOKINETICS
  • SAFETY PHARMACOLOGY STUDIES AND SPECIAL TOXICITY STUDIES
  • DEVELOPMENTAL AND REPRODUCTIVE TOXICITY STUDIES
  • CARCINOGENICITY STUDIES
  • CONCLUDING REMARKS
  • Acknowledgment
  • References
  • 31 - Biocompatibility Evaluation of Medical Devices
  • INTRODUCTION
  • EVALUATION OF THE BIOLOGICAL EFFECTS OF MEDICAL DEVICES
  • CYTOTOXICITY
  • CFU Assay
  • MTT Assay
  • IRRITATION
  • SYSTEMIC TOXICITY
  • GENOTOXICITY
  • CHEMICAL CHARACTERIZATION AND RISK ASSESSMENT
  • References
  • VIII - PREDICTIVE TOXICOLOGY, TOXICOMETABOLOMICS, TOXICOGENOMICS, AND IMAGING
  • 32 - Application of Evolving Computational and Biological Platforms for Chemical Safety Assessment
  • INTRODUCTION
  • NEW NEEDS OF THE 21ST CENTURY REQUIRE NEW APPROACHES
  • A NEW APPROACH: PREDICTIVE TOXICOLOGY
  • Recent History
  • CHEMINFORMATICS AND BIOLOGICAL PROFILING PLATFORMS
  • Cheminformatics
  • Model Organisms
  • Zebrafish Embryo
  • General Description
  • Use in Toxicity Assessment
  • Limitations
  • Caenorhabditis elegans
  • General Description
  • Use in Toxicity Assessment
  • Limitations
  • Mammalian Whole-Embryo and Organotypic Cultures
  • Whole-Embryo Culture
  • General Description
  • Use in Toxicity Assessment
  • Limitations
  • Organ and Tissue Slices
  • General Description
  • Use in Toxicity Assessment
  • Limitations
  • Isolated Tissues to Evaluate Eye Irritation?Potentials
  • General Description
  • Use in Toxicity Assessment
  • Limitations
  • Primary Cultures
  • Primary Hepatocytes
  • General Description
  • Use in Toxicity Assessment
  • Limitations
  • Three-Dimensional Cultures
  • General Description
  • Use in Toxicity Assessment
  • Limitations
  • Cell-Line Models
  • Hepatic Cell Lines
  • General Description
  • Use in Toxicity Assessment
  • Limitations
  • Cell Lines Used in Mutagenicity Testing
  • General Description
  • Use in Toxicity Assessment
  • Limitations
  • Cell Lines for the Assessment of Skin Sensitization Potential
  • General Description
  • Use in Toxicity Assessment
  • Limitations
  • Cell Lines Used to Predict Eye Irritation
  • General Description
  • Use in Toxicity Assessment
  • Limitations
  • Embryonic and Induced Pluripotent Stem Cells
  • General Description
  • Use in Toxicity Assessment
  • Limitations
  • SCENARIOS FOR THE APPLICATION OF PREDICTIVE?TOXICOLOGY
  • Use in the Selection and Evaluation of New?Chemical Analogs
  • Use in Evaluating Existing Chemicals
  • Use in Value-Chain Decisions
  • Future Paradigms for Safety Assessment
  • CONCLUSIONS
  • Acknowledgments
  • References
  • 33 - Toxicometabolomics: Technology and Applications
  • INTRODUCTION TO BIOMARKER DISCOVERY AND VALIDATION?IN TOXICOLOGY
  • ADVANTAGES OF METABOLOMICS IN BIOMARKER DISCOVERY
  • TOXICOMETABOLOMIC PLATFORM TECHNOLOGIES
  • Chemocentric Global Metabolomics
  • Ion-Centric Global Metabolomics
  • Targeted Metabolomics
  • NMR Metabolomics
  • TOXICOMETABOLOMIC APPLICATIONS
  • Fenofibrate
  • Ethylene-Glycol Monomethyl Ether
  • Indoxyl Sulfate
  • Cigarette-Smoke Exposure
  • Pentamethylchromanol
  • The Future of "Omics" Technologies in Toxicity Studies
  • CONCLUDING REMARKS AND FUTURE DIRECTIONS
  • References
  • 34 - Toxicogenomics in Preclinical Development
  • INTRODUCTION
  • TOXICOGENOMICS
  • The Principle of Compound-Induced Alteration in Gene Expression
  • TOXICOGENOMICS APPROACHES
  • Genomic Approaches
  • Genome Sequencing-The Next Generation
  • Genotyping
  • Epigenetics
  • Transcriptomic Approaches
  • Whole-Transcriptome Analysis
  • Customized Transcript Approaches
  • TOXICOGENOMICS TECHNOLOGIES
  • High-Throughput Technologies/Whole-Genome Profiling
  • RNA Isolation
  • cDNA Synthesis
  • Labeling
  • Hybridization
  • Washing
  • Image-Data Acquisition
  • Low-Throughput Technologies/Single-Gene Detection
  • Northern Blot
  • Quantitative Real-Time PCR (TaqMan/SYBR)
  • Branched DNA
  • DATA ANALYSIS-BIOSTATISTICAL ANALYSIS OF GENOMIC?DATA
  • Class Discovery
  • Comparison of Groups and Classes
  • Mechanistic and Network Analysis
  • Toxicological Prediction Models
  • Identification and Qualification of Novel Identified Biomarkers
  • TOXICOGENOMICS IN DRUG DEVELOPMENT
  • EXAMPLES FOR THE USE OF TOXICOGENOMICS IN?PRECLINICAL TOXICOLOGY
  • Genotoxicity
  • Organotoxicity
  • Hepatotoxicity
  • Nephrotoxicity
  • Cardiotoxicity
  • Idiosyncrasy
  • SPECIFIC APPLICATIONS OF TOXICOGENOMICS
  • Mechanistic Information
  • Risk Assessment
  • Variability in Susceptibility
  • Cross-Species Extrapolation
  • STUDY DESIGN OF TOXICOGENOMICS APPROACHES IN PRECLINICAL TOXICOLOGY
  • FUTURE PERSPECTIVES
  • MicroRNA
  • Next-Generation Sequencing
  • Formalin-Fixed, Paraffin-Embedded Tissue
  • CONCLUSION
  • References
  • 35 - Use of Imaging for Preclinical Evaluation
  • MOLECULAR IMAGING TECHNOLOGY AND DRUG?DEVELOPMENT
  • MULTIMODALITY IMAGING TECHNIQUES
  • IMAGING PROBES AND BIOMARKERS
  • FUNCTIONAL MOLECULAR IMAGING TECHNIQUES
  • SINGLE-PHOTON EMISSION COMPUTED TOMOGRAPHY
  • POSITRON-EMISSION TOMOGRAPHY
  • MICRO X-RAY COMPUTED TOMOGRAPHY
  • MAGNETIC RESONANCE IMAGING/MAGNETIC?RESONANCE MICROSCOPY
  • OPTICAL IMAGING
  • ULTRASONOGRAPHY
  • APPLICATIONS OF PRECLINICAL IMAGING
  • Molecular Imaging as an ADME?Platform in Drug Development
  • Imaging in Oncology
  • Imaging CNS Disease
  • Imaging Autoimmune Diseases
  • Imaging Cardiac Disease
  • REMARKS AND FUTURE DIRECTIONS
  • Acknowledgments
  • References
  • Index
  • A
  • B
  • C
  • D
  • E
  • F
  • G
  • H
  • I
  • J
  • K
  • L
  • M
  • N
  • O
  • P
  • Q
  • R
  • S
  • T
  • U
  • V
  • W
  • X
  • Y
  • Z
  • Back Cover

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Das Dateiformat PDF zeigt auf jeder Hardware eine Buchseite stets identisch an. Daher ist eine PDF auch für ein komplexes Layout geeignet, wie es bei Lehr- und Fachbüchern verwendet wird (Bilder, Tabellen, Spalten, Fußnoten). Bei kleinen Displays von E-Readern oder Smartphones sind PDF leider eher nervig, weil zu viel Scrollen notwendig ist. Mit Adobe-DRM wird hier ein "harter" Kopierschutz verwendet. Wenn die notwendigen Voraussetzungen nicht vorliegen, können Sie das E-Book leider nicht öffnen. Daher müssen Sie bereits vor dem Download Ihre Lese-Hardware vorbereiten.

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