Chapter
CHAPTER 1 EMERGING TECHNOLOGIES AND THEIR ROLE IN REGULATORY REVIEW
1.2 SAFETY ASSESSMENT IN DRUG DEVELOPMENT AND REVIEW
1.2.2 PRECLINICAL DEVELOPMENT
1.3 THE ROLE OF NEW TECHNOLOGIES IN REGULATORY SAFETY ASSESSMENT
1.3.1 IN SILICO MODELS FOR TOXICITY PREDICTION
1.3.2 CELL-BASED ASSAYS FOR TOXICITY PREDICTION
PART II SAFETY LEAD OPTIMIZATION STRATEGIES
CHAPTER 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
2.3.2 APPLICATION OF PROSPECTIVE MODELS
2.3.3 APPLICATION OF RETROSPECTIVE MODELS
CHAPTER 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
3.2.1 TARGET SAFETY ASSESSMENT FOR BIOPHARMACEUTICALS TARGETING THE IMMUNE SYSTEM
3.3 STRATEGIC APPROACHES FOR BIOPHARMACEUTICALS AND ADCS
3.3.1 MODALITY-ASSOCIATED RISKS
3.3.5 OFF-TARGET TOXICITY
3.3.6 EVALUATION OF NOVEL WARHEADS
3.3.7 EVALUATION OF NEW ADC TECHNOLOGIES
3.4 PREDICTIVE SAFETY TOOLS FOR LARGE MOLECULES
3.4.2 SPECIALIZED ASSAYS FOR DETECTION OF ADCC, CDC, AND ADCP
3.4.3 IMMUNOTOXICITY TESTING
3.4.4 PREDICTING AND ASSESSING UNINTENDED ADVERSE CONSEQUENCES
3.5 STRATEGIES FOR SPECIES SELECTION
3.6 STRATEGY FOR DOSE-RANGING STUDIES FOR SAFETY EVALUATION OF BIOPHARMACEUTICALS
CHAPTER 4 DISCOVERY AND DEVELOPMENT STRATEGIES FOR SMALL INTERFERING RNAS
4.1.1 RNAI MOLECULAR MECHANISM
4.1.2 CONJUGATE SIRNAS FOR HEPATIC TARGETS
4.2.1 LARGE GENE FAMILIES
4.2.3 GENES WITH RAPID MRNA TURNOVER
4.2.4 SELECTING AMONG ALTERNATE TRANSCRIPT VARIANTS
4.3 SIRNA DESIGN AND SCREENING STRATEGIES
4.3.2 CHEMICAL MODIFICATION OF SIRNA
4.3.3 SCREENING OF SIRNA THERAPEUTICS
4.4 SAFETY LEAD OPTIMIZATION OF SIRNA
4.4.1 IMMUNOSTIMULATION SCREENING
4.4.2 TOXICOLOGY SCREENING IN RODENTS
4.4.3 POINTS TO CONSIDER FOR CHEMICALLY MODIFIED NUCLEOTIDES
4.5 INTEGRATION OF LEAD OPTIMIZATION DATA FOR CANDIDATE SELECTION AND DEVELOPMENT
PART III BASIS FOR IN VITRO–IN VIVO PK TRANSLATION
CHAPTER 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
CHAPTER 6 THE NEED FOR HUMAN EXPOSURE PROJECTION IN THE INTERPRETATION OF PRECLINICAL IN VITRO AND IN VIVO ADME TOX DATA
6.2 METHODOLOGY USED FOR HUMAN PK PROJECTION IN DRUG DISCOVERY
6.2.1 PREDICTION OF PLASMA CONCENTRATION–TIME PROFILE BY USING THE WAJIMA ALLOMETRIC METHOD
6.2.2 PREDICTION OF PLASMA AND TISSUE CONCENTRATION–TIME PROFILES BY USING THE PBPK MODELING APPROACH
6.2.3 INTEGRATIVE APPROACHES OF TOXICITY PREDICTION BASED ON THE EXTENT OF TARGET TISSUE DISTRIBUTION
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
6.3.1 PHRMA INITIATIVE ON THE PREDICTION OF CL
6.3.2 PHRMA INITIATIVE ON THE PREDICTION OF VOLUME OF DISTRIBUTION
6.3.3 PHRMA INITIATIVE ON THE PREDICTION OF CONCENTRATION–TIME PROFILE
6.3.4 LEAD COMMENTARIES ON THE PHRMA INITIATIVE
CHAPTER 7 ADME PROPERTIES LEADING TO TOXICITY
7.3 THE ADME OPTIMIZATION STRATEGY
7.4 CONCLUSIONS AND FUTURE DIRECTIONS
PART IV PREDICTING ORGAN TOXICITY
8.2 DILI MECHANISMS AND SUSCEPTIBILITY
8.3 COMMON MECHANISMS THAT CONTRIBUTE TO DILI
8.3.1 MITOCHONDRIAL INJURY
8.3.2 REACTIVE METABOLITE-MEDIATED TOXICITY
8.3.4 COMPLICITY BETWEEN DUAL INHIBITORS OF BSEP AND MITOCHONDRIAL FUNCTION
8.4 MODELS SYSTEMS USED TO STUDY DILI
8.4.1 HIGH CONTENT IMAGE ANALYSIS
8.4.2 COMPLEX CELL MODELS
8.6 SYSTEMS PHARMACOLOGY AND DILI
9.2 CLASSICAL IN VITRO/EX VIVO ASSESSMENT OF CARDIAC ELECTROPHYSIOLOGIC EFFECTS
9.2.2 SUBCELLULAR TECHNIQUES
9.2.4 AP/REPOLARIZATION ASSAYS
9.2.5 PROARRHYTHMIA ASSAYS
9.2.6 FUTURE DIRECTIONS: STEM CELL-DERIVED CMS
9.3 CARDIAC ION CHANNELS AND IN SILICO PREDICTION
9.3.2 HIGH-THROUGHPUT CARDIAC ION CHANNEL DATA
9.3.3 IN SILICO APPROACHES
9.4 FROM ANIMAL EX VIVO/IN VITRO MODELS TO HUMAN STEM CELL-DERIVED CMS FOR CARDIAC SAFETY TESTING
9.4.2 CURRENTLY AVAILABLE TECHNOLOGIES
9.5 IN VIVO TELEMETRY CAPABILITIES AND PRECLINICAL DRUG DEVELOPMENT
9.5.2 CV SP EVALUATIONS USING TELEMETRY
9.5.3 EVALUATION OF RESPIRATORY FUNCTION USING TELEMETRY
9.5.4 EVALUATION OF CNS USING TELEMETRY
9.5.5 EVALUATION OF OTHER SYSTEMS USING TELEMETRY
9.6 ASSESSMENT OF MYOCARDIAL CONTRACTILITY IN PRECLINICAL MODELS
9.6.2 GOLD STANDARD APPROACHES
9.6.3 IN VITRO AND EX VIVO ASSAYS
9.6.5 TRANSLATION TO CLINIC
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!
CHAPTER 10 PREDICTIVE IN VITRO MODELS FOR ASSESSMENT OF NEPHROTOXICITY AND DRUG–DRUG INTERACTIONS IN VITRO
10.1.1 CONSIDERATIONS FOR STUDYING THE KIDNEYS AS A TARGET ORGAN FOR DRUGS AND TOXIC CHEMICALS
10.1.2 ADVANTAGES AND LIMITATIONS OF IN VITRO MODELS IN GENERAL FOR MECHANISTIC TOXICOLOGY AND SCREENING OF POTENTIAL ADVERSE EFFECTS
10.1.3 TYPES OF IN VITRO MODELS AVAILABLE FOR STUDYING HUMAN KIDNEYS
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
10.3.1 METHODS FOR HPT CELL ISOLATION
10.3.2 VALIDATION OF HPT PRIMARY CELL CULTURES
10.3.3 ADVANTAGES AND LIMITATIONS OF HPT PRIMARY CELL CULTURES
10.3.4 GENETIC POLYMORPHISMS AND INTERINDIVIDUAL SUSCEPTIBILITY
10.4 TOXICOLOGY STUDIES IN HPT PRIMARY CELL CULTURES
10.5 CRITICAL STUDIES FOR DRUG DISCOVERY IN HPT PRIMARY CELL CULTURES
10.5.1 PHASE I AND PHASE II DRUG METABOLISM
10.5.2 MEMBRANE TRANSPORT
10.6 SUMMARY AND CONCLUSIONS
10.6.1 ADVANTAGES AND LIMITATIONS OF PERFORMING STUDIES IN HPT PRIMARY CELL CULTURES
CHAPTER 11 PREDICTING ORGAN TOXICITY IN VITRO: BONE MARROW
11.2 BIOLOGY OF THE HEMATOPOIETIC SYSTEM
11.4 MEASURING HEMOTOXICITY
11.4.1 USES OF THE CFC ASSAY
11.4.2 IN VITRO/IN VIVO CONCORDANCE
11.4.3 LIMITATIONS OF THE CFC ASSAY
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
CHAPTER 12 PREDICTING ORGAN TOXICITY IN VITRO: DERMAL TOXICITY
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
12.4.1 SKIN SENSITIZATION
12.5 MECHANISM-BASED CUTANEOUS ADVERSE EFFECTS
12.5.1 PERCUTANEOUS ABSORPTION
12.5.3 SKIN LIGHTENING/MELANOGENESIS
CHAPTER 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
13.3.1 ACQUIRED IMMUNE RESPONSES
13.3.2 FC. RECEPTOR AND COMPLEMENT BINDING
13.3.3 ASSESSMENT OF HYPERSENSITIVITY
13.3.4 IMMUNOGENICITY OF BIOLOGICS
13.3.5 IMMUNOTOXICITY DUE TO MYELOTOXICITY
CHAPTER 14 STRATEGIES AND ASSAYS FOR MINIMIZING RISK OF OCULAR TOXICITY DURING EARLY DEVELOPMENT OF SYSTEMICALLY ADMINISTERED DRUGS
14.2 IN SILICO AND IN VITRO TOOLS AND STRATEGIES
14.3 HIGHER-THROUGHPUT IN VIVO TOOLS AND STRATEGIES
14.3.1 OCULAR REFLEXES AND ASSOCIATED BEHAVIORS
14.3.2 NONINVASIVE OPHTHALMIC EXAMINATIONS
14.4 STRATEGIES, GAPS, AND EMERGING TECHNOLOGIES
14.4.1 STRATEGIC DEPLOYMENT OF IN SILICO, IN VITRO, AND IN VIVO TOOLS
14.4.2 EMERGING BIOMARKERS OF RETINAL TOXICITY
CHAPTER 15 PREDICTING ORGAN TOXICITY IN VIVO—CENTRAL NERVOUS SYSTEM
15.2 MODELS FOR ASSESSMENT OF CNS ADRS
15.2.1 IN VIVO BEHAVIORAL BATTERIES
15.3 SEIZURE LIABILITY TESTING
15.3.2 MEDIUM/HIGH THROUGHPUT APPROACHES TO ASSESS SEIZURE LIABILITY OF DRUG CANDIDATES
15.3.3 IN VIVO APPROACHES TO ASSESS SEIZURE LIABILITY OF DRUG CANDIDATES
15.4 DRUG ABUSE LIABILITY TESTING
15.4.2 PRECLINICAL MODELS TO TEST ABUSE POTENTIAL OF CNS-ACTIVE DRUG CANDIDATES
CHAPTER 16 BIOMARKERS, CELL MODELS, AND IN VITRO ASSAYS FOR GASTROINTESTINAL TOXICOLOGY
16.2 ANATOMIC AND PHYSIOLOGIC CONSIDERATIONS
16.2.4 SMALL AND LARGE INTESTINE
16.3.1 BIOMARKERS OF EPITHELIAL MASS, INTESTINAL FUNCTION, OR CELLULAR DAMAGE
16.3.2 BIOMARKERS OF INFLAMMATION
16.4 CELL MODELS OF THE GI TRACT
16.4.1 CELL LINES AND PRIMARY CELLS
16.4.2 INDUCED PLURIPOTENT STEM CELLS
16.4.4 3D ORGANOID MODELS
16.5 CELL-BASED IN VITRO ASSAYS FOR SCREENING AND MECHANISTIC INVESTIGATIONS TO GI TOXICITY
16.6 SUMMARY/CONCLUSIONS/CHALLENGES
CHAPTER 17 PRECLINICAL SAFETY ASSESSMENT OF DRUG CANDIDATE-INDUCED PANCREATIC TOXICITY: FROM AN APPLIED PERSPECTIVE
17.1 DRUG-INDUCED PANCREATIC TOXICITY
17.1.2 DRUG-INDUCED PANCREATIC EXOCRINE TOXICITY IN HUMANS: PANCREATITIS
17.1.3 MECHANISMS OF DRUG-INDUCED PANCREATIC TOXICITY
17.2 PRECLINICAL EVALUATION OF PANCREATIC TOXICITY
17.2.2 RISK MANAGEMENT AND UNDERSTANDING THE POTENTIAL FOR CLINICAL TRANSLATION
17.2.3 INTERSPECIES AND INTERSTRAIN DIFFERENCES IN SUSCEPTIBILITY TO PANCREATIC TOXICITY
17.3 PRECLINICAL PANCREATIC TOXICITY ASSESSMENT: IN VIVO
17.3.1 ROUTINE ASSESSMENT
17.3.2 SPECIALIZED TECHNIQUES
17.4 PANCREATIC BIOMARKERS
17.4.2 EXOCRINE INJURY BIOMARKERS IN HUMANS AND PRECLINICAL SPECIES
17.4.3 ENDOCRINE/ISLET FUNCTIONAL BIOMARKERS FOR HUMANS AND PRECLINICAL SPECIES
17.4.4 A NOTE ON BIOMARKERS OF VASCULAR INJURY RELEVANT TO THE PANCREAS
17.4.5 AUTHOR’S OPINION ON THE STRATEGY FOR INVESTMENTS TO ADDRESS PANCREATIC BIOMARKER GAPS
17.5 PRECLINICAL PANCREATIC TOXICITY ASSESSMENT: IN VITRO
17.5.1 INTRODUCTION TO PANCREATIC CELL CULTURE
17.5.2 MODELING IN VIVO TOXICITY IN VITRO, TESTING TRANSLATABILITY, AND IN VITRO SCREENING TOOLS
17.5.3 CASE STUDY 1: DRUG CANDIDATE-INDUCED DIRECT ACINAR CELL TOXICITY IN VIVO WITH CONFIRMATION OF TOXICITY AND DRUG CANDIDATE SCREENING IN VITRO
17.5.4 CASE STUDY 2: DRUG CANDIDATE-INDUCED MICROVASCULAR INJURY AT THE EXOCRINE–ENDOCRINE INTERFACE IN THE RAT WITH UNSUCCESSFUL CONFIRMATION OF TOXICITY IN VITRO AND NO PANCREAS-SPECIFIC MONITORABLE BIOMARKERS IDENTIFIED
17.5.5 EMERGING TECHNOLOGIES/GAPS: ORGANOTYPIC MODELS
17.6 SUMMARY AND CONCLUSIONS
PART V ADDRESSING THE FALSE NEGATIVE SPACE—INCREASING PREDICTIVITY
CHAPTER 18 ANIMAL MODELS OF DISEASE FOR FUTURE TOXICITY PREDICTIONS
18.2 HEPATIC DISEASE MODELS
18.2.1 HEPATIC TOXICITY: RELEVANCE TO DRUG ATTRITION
18.2.2 HEPATIC TOXICITY: REASONS FOR POOR TRANSLATION FROM ANIMAL TO HUMAN
18.2.3 AVAILABLE HEPATIC MODELS TO PREDICT HEPATIC TOXICITY OR UNDERSTAND MOLECULAR MECHANISMS OF TOXICITY: ADVANTAGES AND LIMITATIONS
18.3 CARDIOVASCULAR DISEASE MODELS
18.3.1 CARDIAC TOXICITY: RELEVANCE TO DRUG ATTRITION
18.3.2 CARDIAC TOXICITY: REASONS FOR POOR TRANSLATION FROM ANIMAL TO HUMAN
18.3.3 AVAILABLE CV MODELS TO PREDICT CARDIAC TOXICITY OR UNDERSTAND MOLECULAR MECHANISMS OF TOXICITY: ADVANTAGES AND LIMITATIONS
18.4 NERVOUS SYSTEM DISEASE MODELS
18.4.1 NERVOUS SYSTEM TOXICITY: RELEVANCE TO DRUG ATTRITION
18.4.2 NERVOUS SYSTEM TOXICITY: REASONS FOR POOR TRANSLATION FROM ANIMAL TO HUMAN
18.4.3 AVAILABLE NERVOUS SYSTEM MODELS TO PREDICT NERVOUS SYSTEM TOXICITY OR UNDERSTAND MOLECULAR MECHANISMS OF TOXICITY: ADVANTAGES AND LIMITATIONS
18.5 GASTROINTESTINAL INJURY MODELS
18.5.1 GASTROINTESTINAL (GI) TOXICITY: RELEVANCE TO DRUG ATTRITION
18.5.2 GASTROINTESTINAL TOXICITY: REASONS FOR POOR TRANSLATION FROM ANIMAL TO HUMAN
18.5.3 AVAILABLE GASTROINTESTINAL ANIMAL MODELS TO PREDICT GASTROINTESTINAL TOXICITY OR UNDERSTAND MOLECULAR MECHANISMS OF TOXICITY: ADVANTAGES AND LIMITATIONS
18.6.1 RENAL TOXICITY: RELEVANCE TO DRUG ATTRITION
18.6.2 RENAL TOXICITY: REASONS FOR POOR TRANSLATION FROM ANIMAL TO HUMAN
18.6.3 AVAILABLE RENAL MODELS TO PREDICT RENAL TOXICITY OR UNDERSTAND MOLECULAR MECHANISMS OF TOXICITY: ADVANTAGES AND LIMITATIONS
18.7 RESPIRATORY DISEASE MODELS
18.7.1 RESPIRATORY TOXICITY: RELEVANCE TO DRUG ATTRITION
18.7.2 RESPIRATORY TOXICITY: REASONS FOR ADEQUATE TRANSLATION FROM ANIMAL TO HUMAN
18.7.3 AVAILABLE RESPIRATORY MODELS TO PREDICT RESPIRATORY TOXICITY OR UNDERSTAND MOLECULAR MECHANISMS OF TOXICITY: ADVANTAGES AND LIMITATIONS
CHAPTER 19 THE USE OF GENETICALLY MODIFIED ANIMALS IN DISCOVERY TOXICOLOGY
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
19.4.3 NUCLEAR RECEPTORS AND COORDINATE INDUCTION
19.4.4 HUMANIZED LIVER MODELS
CHAPTER 20 MOUSE POPULATION -BASED TOXICOLOGY FOR PERSONALI ZED MEDICINE AND IMPROVED SAFETY PREDICTION
20.2 PHARMACOGENETICS AND POPULATION VARIABILITY
20.3 RODENT POPULATIONS ENABLE A POPULATION-BASED APPROACH TO TOXICOLOGY
20.3.1 MOUSE DIVERSITY PANEL
20.4 APPLICATIONS FOR PHARMACEUTICAL SAFETY SCIENCE
20.4.1 PERSONALIZED MEDICINE: DEVELOPMENT OF COMPANION DIAGNOSTICS
20.4.2 BIOMARKERS OF SENSITIVITY
20.5 STUDY DESIGN CONSIDERATIONS FOR GENOMIC MAPPING
20.5.5 GENOME-WIDE ASSOCIATION ANALYSIS
20.5.6 CANDIDATE GENE ANALYSIS
20.5.7 COST CONSIDERATIONS
PART VI STEM CELLS IN TOXICOLOGY
CHAPTER 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
21.2.1 PRIMARY HUMAN HEPATOCYTES
21.4 CHALLENGES OF USING IPSCS AND NEW DIRECTIONS FOR IMPROVEMENT
21.4.1 COMPLEX CULTURE SYSTEMS
21.4.4 PERFUSION BIOREACTORS
21.5 ALTERNATE USES OF HLCS IN TOXICITY ASSESSMENT
CHAPTER 22 HUMAN PLURIPOTENT STEM CELL-DERIVED CARDIOMYOCYTES: A NEW PARADIGM IN PREDICTIVE PHARMACOLOGY AND TOXICOLOGY
22.2 ADVENT OF HPSCS: REPROGRAMMING AND CARDIAC DIFFERENTIATION
22.2.2 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
22.5.1 TARGET IDENTIFICATION AND VALIDATION: “CLINICAL TRIAL IN A DISH”
22.5.2 SAFETY PHARMACOLOGY AND TOXICOLOGICAL TESTING
22.6 LIMITATIONS AND CHALLENGES
22.7 CONCLUSIONS AND FUTURE PERSPECTIVE
CHAPTER 23 STEM CELL-DERIVED RENAL CELLS AND PREDICTIVE RENAL IN VITRO MODELS
23.2 PROTOCOLS FOR THE DIFFERENTIATION OF PLURIPOTENT STEM CELLS INTO CELLS OF THE RENAL LINEAGE
23.2.1 EARLIER PROTOCOLS AND THE RECENT RACE
23.2.2 PROTOCOLS DESIGNED TO MIMIC EMBRYONIC KIDNEY DEVELOPMENT
23.2.3 RAPID AND EFFICIENT METHODS FOR THE GENERATION OF PROXIMAL TUBULAR-LIKE CELLS
23.3 RENAL IN VITRO MODELS FOR DRUG SAFETY SCREENING
23.3.1 MICROFLUIDIC AND 3D MODELS AND OTHER MODELS THAT HAVE BEEN TESTED WITH LOWER NUMBERS OF COMPOUNDS
23.3.2 IN VITRO MODELS THAT HAVE BEEN TESTED WITH HIGHER NUMBERS OF COMPOUNDS AND THE FIRST PREDICTIVE RENAL IN VITRO MODEL
23.3.3 STEM CELL-BASED PREDICTIVE MODELS
23.4 ACHIEVEMENTS AND FUTURE DIRECTIONS
PART VII CURRENT STATUS OF PRECLINICAL IN VIVO TOXICITY BIOMARKERS
CHAPTER 24 PREDICTIVE CARDIAC HYPERTROPHY BIOMARKERS IN NONCLINICAL STUDIES
24.1 INTRODUCTION TO BIOMARKERS
24.2 CARDIOVASCULAR TOXICITY
24.4 DIAGNOSIS OF CARDIAC HYPERTROPHY
24.5 BIOMARKERS OF CARDIAC HYPERTROPHY
CHAPTER 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
CHAPTER 26 NOVEL TRANSLATIONAL BIOMARKERS OF SKELETAL MUSCLE INJURY
26.2 OVERVIEW OF DRUG-INDUCED SKELETAL MUSCLE INJURY
26.3 NOVEL BIOMARKERS OF DRUG-INDUCED SKELETAL MUSCLE INJURY
26.3.1 SKELETAL TROPONIN I (STNI)
26.3.2 CREATINE KINASE M (CKM)
26.3.3 MYOSIN LIGHT CHAIN 3 (MYL3)
26.3.4 FATTY ACID-BINDING PROTEIN 3
26.4 REGULATORY ENDORSEMENT
26.5 GAPS AND FUTURE DIRECTIONS
CHAPTER 27 TRANSLATIONAL MECHANISTIC BIOMARKERS AND MODELS FOR PREDICTING DRUG-INDUCED LIVER INJURY: CLINICAL TO IN VITRO PERSPECTIVES
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
27.4.1 GLUTAMATE DEHYDROGENASE
27.4.3 HIGH-MOBILITY GROUP BOX-1 (HMGB1)
27.4.5 MICRORNA-122 (MIR-122)
27.5 IN VITRO MODELS AND THE PREDICTION OF HUMAN DILI
27.6 CONCLUSIONS AND FUTURE PERSPECTIVES
PART VIII KIDNEY INJURY BIOMARKERS
CHAPTER 28 ASSESSING AND PREDICTING DRUG-INDUCED KIDNEY INJURY, FUNCTIONAL CHANGE, AND SAFETY IN PRECLINICAL STUDIES IN RATS
28.2 KIDNEY FUNCTIONAL BIOMARKERS (GLOMERULAR FILTRATION AND TUBULAR REABSORPTION)
28.2.1 TRADITIONAL FUNCTIONAL BIOMARKERS
28.2.2 NOVEL FUNCTIONAL BIOMARKERS
28.3 NOVEL KIDNEY TISSUE INJURY BIOMARKERS
28.3.1 URINARY N-ACETYL-ß-D-GLUCOSAMINIDASE (NAG)
28.3.2 URINARY GLUTATHIONE S-TRANSFERASE A (A-GST)
28.3.3 URINARY RENAL PAPILLARY ANTIGEN 1 (RPA-1)
28.3.4 URINARY CALBINDIN D28
28.4 NOVEL BIOMARKERS OF KIDNEY TISSUE STRESS RESPONSE
28.4.1 URINARY KIDNEY INJURY MOLECULE-1 (KIM-1)
28.4.3 URINARY NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN (NGAL)
28.4.4 URINARY OSTEOPONTIN (OPN)
28.4.5 URINARY L-TYPE FATTY ACID-BINDING PROTEIN (L-FABP)
28.4.6 URINARY INTERLEUKIN-18 (IL-18)
28.5 APPLICATION OF AN INTEGRATED RAT PLATFORM (AUTOMATED BLOOD SAMPLING AND TELEMETRY, ABST) FOR KIDNEY FUNCTION AND INJURY ASSESSMENT
CHAPTER 29 CANINE KIDNEY SAFETY PROTEIN BIOMARKERS
29.2 NOVEL CANINE RENAL PROTEIN BIOMARKERS
29.3 EVALUATIONS OF NOVEL CANINE RENAL PROTEIN BIOMARKER PERFORMANCE
CHAPTER 30 TRADITIONAL KIDNEY SAFETY PROTEIN BIOMARKERS AND NEXT-GENERATION DRUG-INDUCED KIDNEY INJURY BIOMARKERS IN NONHUMAN PRIMATES
30.2 EVALUATIONS OF NOVEL NHP RENAL PROTEIN BIOMARKER PERFORMANCE
30.3 NEW HORIZONS: URINARY MICRORNAS AND NEPHROTOXICITY IN NHPS
CHAPTER 31 RAT KIDNEY MICRORNA ATLAS
CHAPTER 32 MICRORNAS AS NEXT-GENERATION KIDNEY TUBULAR INJURY BIOMARKERS IN RATS
CHAPTER 33 MICRORNAS AS NOVEL GLOMERULAR INJURY BIOMARKERS IN RATS
33.2 RAT GLOMERULAR MIRNAS
CHAPTER 34 INTEGRATING NOVEL IMAGING TECHNOLOGIES TO INVESTIGATE DRUG-INDUCED KIDNEY TOXICITY
CHAPTER 35 IN VITRO TO IN VIVO RELATIONSHIPS WITH RESPECT TO KIDNEY SAFETY BIOMARKERS
35.1 RENAL CELL LINES AS TOOLS FOR TOXICOLOGICAL INVESTIGATIONS
35.2 MECHANISTIC APPROACHES AND IN VITRO TO IN VIVO TRANSLATION
CHAPTER 36 CASE STUDY: FULLY AUTOMATED IMAGE ANALYSIS OF PODOCYTE INJURY BIOMARKER EXPRESSION IN RATS
36.2 MATERIAL AND METHODS
CHAPTER 37 CASE STUDY: NOVEL RENAL BIOMARKERS TRANSLATION TO HUMANS
37.2 IMPLEMENTATION OF TRANSLATIONAL RENAL BIOMARKERS IN DRUG DEVELOPMENT
CHAPTER 38 CASE STUDY: MICRORNAS AS NOVEL KIDNEY INJURY BIOMARKERS IN CANINES
38.2 MATERIAL AND METHODS
CHAPTER 39 NOVEL TESTICULAR INJURY BIOMARKERS
39.3 POTENTIAL BIOMARKERS FOR TESTICULAR TOXICITY
39.3.2 ANDROGEN-BINDING PROTEIN
39.3.4 EMERGING NOVEL APPROACHES
PART IX BEST PRACTICES IN BIOMARKER EVALUATIONS
CHAPTER 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
CHAPTER 41 BEST PRACTICES IN NOVEL BIOMARKER ASSAY FIT-FOR-PURPOSE TESTING
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
41.5.3 PRECISION AND ACCURACY OF THE CALIBRATION CURVE
41.5.4 LOWER LIMIT OF QUANTIFICATION
41.5.5 UPPER LIMIT OF QUANTIFICATION
41.5.6 LIMIT OF DETECTION
41.5.7 PRECISION ASSESSMENT FOR BIOLOGICAL SAMPLES
41.5.8 DILUTIONAL LINEARITY AND PARALLELISM
41.6 SPECIES- AND GENDER-SPECIFIC REFERENCE RANGES
41.8 ADDITIONAL METHOD PERFORMANCE EVALUATIONS
CHAPTER 42 BEST PRACTICES IN EVALUATING NOVEL BIOMARKER FIT FOR PURPOSE AND TRANSLATABILITY
42.2 PROTOCOL DEVELOPMENT
42.3 ASSEMBLING AN OPERATIONS TEAM
42.4 TRANSLATABLE BIOMARKER USE
42.6 BIOLOGICAL MATRIX SELECTION
42.7 DOCUMENTATION OF PATIENT FACTORS
42.8 HUMAN SAMPLE COLLECTION PROCEDURES
42.8.1 BIOMARKERS IN HUMAN TISSUE BIOPSY AND BIOFLUID SAMPLES
42.9 CHOICE OF COLLECTION DEVICE
42.9.1 TISSUE COLLECTION DEVICE
42.9.2 PLASMA COLLECTION DEVICE
42.9.3 SERUM COLLECTION DEVICE
42.9.4 URINE COLLECTION DEVICE
42.10 SCHEDULE OF COLLECTIONS
42.11 HUMAN SAMPLE QUALITY ASSURANCE
42.11.1 MONITORING COMPLIANCE TO SAMPLE COLLECTION PROCEDURES
42.11.2 DOCUMENTING TIME AND TEMPERATURE FROM SAMPLE COLLECTION TO PROCESSING
42.11.3 OPTIMAL HANDLING AND PRESERVATION METHODS
42.11.4 CHOICE OF SAMPLE STORAGE TUBES
42.11.5 CHOICE OF SAMPLE LABELING
42.11.6 OPTIMAL SAMPLE STORAGE CONDITIONS
42.13 DATABASE CONSIDERATIONS
CHAPTER 43 BEST PRACTICES IN TRANSLATIONAL BIOMARKER DATA ANALYSIS
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
CHAPTER 44 TRANSLATABLE BIOMARKERS IN DRUG DEVELOPMENT: REGULATORY ACCEPTANCE AND QUALIFICATION
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
CHAPTER 45 TOXICOGENOMICS IN DRUG DISCOVERY TOXICOLOGY: HISTORY, METHODS, CASE STUDIES, AND FUTURE DIRECTIONS
45.1 A BRIEF HISTORY OF TOXICOGENOMICS
45.2 TOOLS AND STRATEGIES FOR ANALYZING TOXICOGENOMICS DATA
45.3 DRUG DISCOVERY TOXICOLOGY CASE STUDIES
45.3.1 CASE STUDIES: DIAGNOSTIC TOXICOGENOMICS
45.3.2 CASE STUDIES: PREDICTIVE TOXICOGENOMICS
45.3.3 CASE STUDIES: MECHANISTIC/INVESTIGATIVE TOXICOGENOMICS
45.3.4 FUTURE DIRECTIONS IN DRUG DISCOVERY TOXICOGENOMICS
CHAPTER 46 ISSUE INVESTIGATION AND PRACTICES IN DISCOVERY TOXICOLOGY
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
Drug Discovery Toxicology
：From Target Assessment to Translational Biomarkers
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