Predictive toxicology: from vision to reality
Gespeichert in:
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| Format: | Buch |
| Sprache: | English |
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Weinheim
Wiley-VCH
2015
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| Schriftenreihe: | Methods and principles in medicinal chemistry
64 |
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| Online-Zugang: | Inhaltstext Inhaltsverzeichnis |
| Beschreibung: | XXV, 404 S. graph. Darst. 240 mm x 170 mm |
| ISBN: | 9783527336081 9783527674183 |
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CONTENTS
LIST OF CONTRIBUTORS XV
PREFACE XXI
A PERSONAL FOREWORD XXIII
1 INTRODUCTION TO PREDICTIVE TOXICOLOGY TOOLS AND METHODS 1
LAURA SUTER-DICK
AND FRIEDLIEB
PFANNKUCH
1.1 COMPUTATIONAL TOOLS AND BIOINFORMATICS 1
1.1.1
IN SILICO
PREDICTION TOOLS
1
1.1.2 BIOINFORMATICS 2
1.2 OMICS TECHNOLOGIES 2
1.2.1 TOXICOGENOMICS (TRANSCRIPTOMICS) 2
1.2.2 PROTEOMICS 3
1.2.3 METABOLOMICS 3
1.3 DATA INTERPRETATION AND KNOWLEDGE MANAGEMENT 4
1.4 BIOMARKER DEVELOPMENT 4
1.5 ADVANCED IN VITRO SYSTEMS AND STEM CELL RESEARCH 4
1.5.1 ADVANCED IN VITRO TESTING 4
1.5.2 STEM CELL RESEARCH 5
1.6 IMMUNOGENICITY 6
1.7 INTEGRATION AND VALIDATION 7
1.7.1 USE OF OMICS FOR TOXICOLOGY TESTING 7
1.7.2 INTEGRATION OF "NEW" TECHNOLOGIES INTO RISK ASSESSMENT 7
1.7.3 USE OF HUMAN-DERIVED CELLULAR SYSTEMS 8
1.7.4 "GENERAL" ACCEPTANCE - TRANSLATION INTO GUIDELINES 8
1.8 RESEARCH INITIATIVE/COLLABORATIONS 9
1.9 CONCLUDING REMARKS 9
REFERENCES 9
2 IN SILICO TOXICOLOGY - CURRENT APPROACHES AND FUTURE PERSPECTIVES
TO PREDICT TOXIC EFFECTS WITH COMPUTATIONAL TOOLS 11
THOMAS STEGER-HARTMANN
2.1 INTRODUCTION 11
HTTP://D-NB.INFO/1051706858
VI | CONTENTS
2.2 PREDICTION OF HAZARD 11
2.2.1 DEFINITION OF HAZARD AND ITS USE 11
2.2.2 PREDICTION OF MUTAGENICITY 12
2.2.3 PREDICTION OF PHOSPHOLIPIDOSIS 13
2.2.4 PREDICTION OF CARCINOGENICITY 14
2.2.5 PREDICTION OF SKIN SENSITIZATION 14
2.2.6 PREDICTION OF SKIN AND EYE IRRITATION 16
2.2.7 APPROACHES TO SYSTEMIC TOXICITY PREDICTION 17
2.2.7.1 THE CRAMER CLASSES 17
2.2.7.2 PREDICTING TOXIC DOSES OF DRUGS 18
2.2.73 PREDICTING ORGAN TOXICITY 18
2.2.7.4 ADVERSE OUTCOME PATHWAYS AND POTENTIAL FOR PREDICTION 20
2.3 PREDICTION OF RISK 21
2.3.1 RISK DEFINITION AND SOME BASIC CONSIDERATIONS 21
2.3.2 DATA AVAILABILITY 23
2.3.3 DATABASE STRUCTURE AND DATA CURATION 24
2.3.4 APPROACHES TO MODEL AND PREDICT RISK 26
2.4 THOUGHTS ON VALIDATION 27
2.5 CONCLUSIONS AND OUTLOOK 28
REFERENCES 28
3 IN SILICO APPROACHES: DATA MANAGEMENT - BIOINFORMATICS 33
ARND BRANDENBURG, HANS GMUENDER, AND TIMO WITTENBERGER
3.1 INTRODUCTION 33
3.2 EXPERIMENTAL SETUP AND STATISTICAL POWER 34
3.3 PROPERTIES OF DIFFERENT OMICS DATA 35
3.3.1 NEXT-GENERATION SEQUENCING DATA 35
3.3.2 DNA METHYLATION DATA 36
3.3.3 MIRNA DATA 36
3.3.4 CNV AND SNP DATA 36
3.3.5 CHLP-SEQ DATA 37
3.3.6 GENE EXPRESSION MICROARRAY DATA (ASYMETRIX) 37
3.3.7 MASS SPECTROMETRY DATA 38
3.3.8 MISSING VALUES AND ZERO VALUES 40
3.3.9 DATA NORMALIZATION 40
3.4 STATISTICAL METHODS 41
3.4.1 DATA OVERVIEWS 41
3.4.2 NULL HYPOTHESIS/TYPE I AND TYPE II ERRORS 42
3.4.3 MULTIPLE TESTING METHODS 42
3.4.4 STATISTICAL TESTS 43
3.4.5 LINEAR MODELS AND LINEAR MIXED MODELS 43
3.5 PREDICTION AND CLASSIFICATION 44
3.5.1 OVERVIEW 44
3.5.2 GENERATING A REFERENCE COMPENDIUM OF COMPOUNDS 45
3.5.3 CROSS-VALIDATION 46
3.5.4 SELECTION BIAS 47
CONTENTS | VII
3.6 COMBINING DIFFERENT OMICS DATA AND BIOLOGICAL INTERPRETATIONS 47
3.7 DATA MANAGEMENT 48
REFERENCES 51
4 ROLE OF MODELING AND SIMULATION IN TOXICOLOGY PREDICTION S3
ANTJE-CHRISTINE WALZ, HANS PETER GRIMM, CHRISTOPHE MEILLE,
ANTONELLO CARUSO, NEIL PARROTT, AND THIERRY
LAVE
4.1 INTRODUCTION 53
4.2 THE NEED TO BRING PK AND PD IN PREDICTIVE MODELS TOGETHER 54
4.2.1 PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING 54
4.2.2 MATHEMATICAL (PBPK, PK/PD) MODELING 55
4.2.3 PREDICTIVE TOOLS 55
4.3 METHODOLOGICAL ASPECTS AND CONCEPTS 56
4.3.1 "CASCADING" DRUG EFFECTS 56
4.3.2 LINKING EXPOSURE AND EFFECT 57
4.3.3 RECEPTOR OCCUPANCY/ENZYME INHIBITION 57
4.3.4 TRANSDUCTION INTO IN VIVO RESPONSE 57
4.3.4.1 INDIRECT RESPONSE MODELS 58
4.3.4.2 TRANSIT COMPARTMENT MODELS 58
4.3.5 DISEASE MODELING 59
4.4 APPLICATION DURING LEAD OPTIMIZATION 60
4.4.1 EXAMPLE 1: PK/PD MODELING FOR IDENTIFYING THE THERAPEUTIC WINDOW
BETWEEN AN EFFICACY AND A SAFETY RESPONSE 60
4.5 APPLICATION DURING CLINICAL CANDIDATE SELECTION 62
4.5.1 EXAMPLE 2: TRANSLATIONAL PK/PD MODELING TO SUPPORT GO/NO GO
DECISIONS 63
4.6 ENTRY-INTO-HUMAN PREPARATION AND TRANSLATIONAL PK/PD
MODELING 65
4.6.1 SELECTION OF SAFE AND PHARMACOLOGICALLY ACTIVE DOSE FOR ANTICANCER
DRUGS 65
4.6.1.1 EXAMPLE 3 65
4.6.1.2 EXAMPLE 4 67
4.6.2 PK/PD FOR TOXICOLOGY STUDY DESIGN AND EVALUATION 67
4.6.2.1 EXAMPLE 5 67
4.6.2.2 EXAMPLE 6
68
4.6.2.3 EXAMPLE 7
68
4.7 JUSTIFICATION OF STARTING DOSE, CALCULATION OF SAFETY MARGINS, AND
SUPPORT OF PHASE I CLINICAL TRIAL DESIGN 69
4.8 OUTLOOK AND CONCLUSIONS 70
REFERENCES 71
5 GENOMIC APPLICATIONS FOR ASSESSING TOXICITIES OF LIVER
AND KIDNEY INJURY 73
PHILIP HEWITT AND
ESTHER JOHANN
5.1 INTRODUCTION 73
5.1.1 TOXICOGENOMICS IN DRUG DEVELOPMENT 73
VIII
| CONTENTS
5.2 TOXICOGENOMIC APPROACHES 75
5.2.1 HIGH-THROUGHPUT EXPRESSION PROFILES AND DNA
MICROARRAYS 75
5.2.2 DATA ANALYSIS 76
5.3 SPECIFIC APPLICATIONS OF TOXICOGENOMICS 77
5.3.1 MECHANISTIC TOXICOGENOMICS AND RISK ASSESSMENT 77
5.3.2 TOXICOGENOMIC PROFILING OF HEPATOTOXICITY 78
5.3.2.1 HEPATOTOXICITY IN DRUG DEVELOPMENT 78
5.3.3 FUNCTIONAL AND STRUCTURAL PROPERTIES OF THE LIVER 78
5.3.4 LIVER MORPHOLOGY 79
5.3.5 CELL TYPES 80
5.3.6 FUNCTIONAL GRADIENTS 80
5.4 TOXICOGENOMIC APPLICATIONS FOR THE BETTER UNDERSTANDING
OF HEPATOTOXICITY 80
5.4.1 MECHANISTIC TOXICOLOGY 80
5.4.2 CLASS IDENTIFICATION 82
5.4.3 PREDICTIVE TOXICOLOGY 83
5.4.4 IN VITRO CLASSIFIERS OF HEPATOTOXICITY 84
5.4.5 BIOMARKER IDENTIFICATION 84
5.5 TOXICOGENOMIC PROFILING OF NEPHROTOXICITY
86
5.5.1 TOXICOGENOMIC APPROACHES IN NEPHROTOXICITY
86
5.5.2 FINDING GENES THAT MATTER IN AKI 87
5.5.3 SEARCHING FOR NEW BIOMARKERS OF KIDNEY INJURY
88
5.6 LIMITATIONS OF TOXICOGENOMICS 90
5.6.1 IDIOSYNCRASIES 90
5.6.2 EPIGENETICS 91
5.7 CONCLUSIONS 91
REFERENCES 92
6 USE OF TOXICOGENOMICS FOR MECHANISTIC CHARACTERIZATION
OF HEPATOCARCINOGENS IN SHORTER TERM STUDIES 97
HEIDRUN ELLINGER-ZIEGELBAUER
6.1 INTRODUCTION 97
6.1.1 RODENT CARCINOGENICITY TESTING 97
6.1.2 CLASSES OF CARCINOGENS 99
6.2 TOXICOGENOMICS 99
6.2.1 MECHANISTIC TOXICOGENOMIC ANALYSIS AFTER SHORT-TERM TREATMENT
WITH RODENT HEPATOCARCINOGENS 99
6.2.2 APPROACHES FOR PREDICTION OF POTENTIAL HEPATOCARCINOGENS BASED
ON GENE EXPRESSION PROFILING 104
6.2.3 RECENT DEVELOPMENTS: TRANSCRIPTIONAL BENCHMARK DOSE MODELING
BASED ON FUNCTIONAL ANALYSES 119
6.2.4 RECENT OPPORTUNITIES: PUBLICLY AVAILABLE DATA 120
6.3 CONCLUSIONS AND OUTLOOK 123
REFERENCES 123
CONTENTS | IX
7 DISCOVERY AND APPLICATION OF NOVEL BIOMARKERS 129
TIMOTHY W. GANT, EMMA L MARCZYLO, AND MARTIN 0. LEONARD
7.1 INTRODUCTION 129
7.1.1 NEW TECHNOLOGIES GIVE RISE TO NOVEL OPPORTUNITIES FOR BIOMARKER
DISCOVERY 130
7.2 NOVEL RNA BIOMARKERS 131
7.2.1 THE COMPLEX RNA BIOMARKER IN CANCER 131
1.2.2 THE COMPLEX RNA BIOMARKER IN TOXICOLOGY 133
7.2.3 CONNECTIVITY MAPPING WITH THE COMPLEX RNA BIOMARKER FOR HAZARD
IDENTIFICATION 134
7.2.4 MIRNA BIOMARKERS 135
7.3 DNA AS A BIOMARKER 138
7.3.1 DNA POLYMORPHISMS AS FUTURE BIOMARKERS OF DISEASE AND XENOBIOTIC
SUSCEPTIBILITY 138
7.3.2 DNA AND PROTEIN ADDUCT BIOMARKERS 140
7.3.3 EPIGENETIC BIOMARKERS 140
7A NOVEL BIOMARKERS: BEYOND NUCLEOTIDE-BASED DISCOVERY 143
7.5 SUMMARY AND OUTLOOK 145
REFERENCES 146
8 PREDICTIVE TOXICOLOGY: GENETICS, GENOMICS, EPIGENETICS,
AND NEXT-GENERATION SEQUENCING IN TOXICOLOGY 151
TOBIAS HECKEL AND
LAURA SUTER-DICK
8.1 INTRODUCTION 151
8.2 TECHNOLOGICAL ADVANCES 152
8.3 APPLICATIONS IN TOXICOLOGY 154
8.3.1 GENOME SEQUENCING AND SEQUENCE LEVEL COMPARISONS 154
8.3.2 GENOTYPE AND METABOLISM 157
8.3.3 MECHANISTIC TOXICOLOGY AND TOXICOGENOMICS 160
8.3.4 EPIGENETIC CHANGES AND MIRNAS 162
8.4 SUMMARY AND OUTLOOK 164
REFERENCES 165
9 BIOMARKERS AS TOOLS FOR PREDICTIVE SAFETY ASSESSMENT:
NOVEL MARKERS OF DRUG-INDUCED KIDNEY INJURY 171
ANGELA MALTY
9.1 NEED AND SEARCH FOR NOVEL BIOMARKERS OF KIDNEY INJURY 171
9.2 URINARY BIOMARKERS OF DRUG-INDUCED KIDNEY INJURY 172
9.2.1 STRUCTURE AND FUNCTION OF NOVEL URINARY BIOMARKERS 172
9.2.1.1 KIDNEY INJURY MOLECULE-1 172
9.2.1.2 CLUSTERIN 174
9.2.1.3 CYSTATIN C 175
9.2.1.4 P
2
-MICROGLOBULIN 175
9.2.1.5 LIVER-TYPE FATTY ACID BINDING PROTEIN 175
9.2.1.6 NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN 176
X| CONTENTS
9.2.1.7 OTHERS 176
9.2.2 EXPERIMENTAL AND CLINICAL SUPPORT FOR THE USE OF NOVEL URINARY
BIOMARKERS FOR THE DETECTION AND PREDICTION OF ACUTE KIDNEY
INJURY 177
9.2.2.1 PERFORMANCE OF NOVEL URINARY BIOMARKERS IN PRECLINICAL MODELS OF
RENAL INJURY 177
9.2.2.2 CLINICAL SUPPORT FOR NOVEL URINARY KIDNEY INJURY BIOMARKERS 178
9.3 GENOMIC BIOMARKERS 179
9.3.1 INDIVIDUAL GENES 179
9.3.2 BIOMARKER PANELS AND GENE SIGNATURES 180
9.3.3 MICRORNAS 181
9.4 QUALIFICATION AND USE OF NOVEL KIDNEY INJURY BIOMARKERS IN
PRECLINICAL
SAFETY ASSESSMENT 182
9.4.1 BIOMARKER QUALIFICATION AND REGULATORY ACCEPTANCE 182
9.4.2 APPLICATION OF NOVEL RENAL SAFETY MARKERS TO PRECLINICAL DECISION
MAKING 183
9.4.3 TECHNOLOGICAL ASPECTS 184
9.5 SUMMARY AND PERSPECTIVES 185
REFERENCES 186
10 THE USE OF RENAL CELL CULTURE FOR NEPHROTOXICITY INVESTIGATIONS
195
ANJA WILMES AND PAUL JENNINGS
10.1 INTRODUCTION 195
10.2 IN VITRO RENAL MODELS 196
10.2.1 CHARACTERIZATION 197
10.2.2 IMMORTALIZATION OF PRIMARY CELLS 199
10.2.3 AVAILABLE PODOCYTE AND PROXIMAL TUBULE CELL LINES 201
10.3 STEM CELLS 202
10.4 OPTIMAL CELL CULTURE CONDITIONS 206
10.5 IN VITRO NEPHROTOXICITY ASSESSMENT 208
10.6 OUTLOOK 209
REFERENCES 210
'11 THE ZEBRAFISH MODEL IN TOXICOLOGY
217
NATALIE MESENS
11.1 THE NEED FOR A PHYSIOLOGICALLY RELEVANT ORGAN MODEL IN
DRUG TOXICITY TESTING 217
11.2 EXTENSIVE KNOWLEDGE ABOUT GENETICS, DEVELOPMENT,
AND PHYSIOLOGY OF D. RERIO 219
11.3 STUDIES OF SPECIFIC ORGAN TOXICITIES IN ZEBRAFISH EMBRYOS
AND LARVAE 220
11.3.1 CARDIOTOXICITY 220
11.3.2 NEUROTOXICITY 221
11.3.3 HEPATOTOXICITY 222
11.3.4 TERATOGENICITY 226
CONTENTS IXI
11.3.5 FUTURE DIRECTIONS: ADME STUDIES AND FUTURE EXPLORATIVE
RESEARCH 231
11.3.5.1 ABSORPTION AND DISTRIBUTION 231
11.3.5.2 METABOLISM 232
11.3.5.3 HARMONIZATION AND VALIDATION 232
11.3.5.4 FUTURE EXPLORATIVE RESEARCH 234
REFERENCES 234
12 PREDICTIVE METHOD DEVELOPMENT: CHALLENGES FOR COSMETICS
AND GENOTOXICITY AS A CASE STUDY 241
GLADYS OUIDRAOGO, FABRICE
NESSLANY, SOPHIE SIMAR, SMAIL TALAHARI,
DORIS LAGACHE,
ERIC VERCAUTEREN, LAUREN
NAKAB, ASTRID MAYOUX,
BRIGITTE FAQUET, AND NICOLE
FLAMAND
12.1 INTRODUCTION 241
12.2 THE TOOLBOX OF PREDICTIVE METHODS 243
12.2.1 IN SILICO TOOLS 243
12.2.2 BIOCHEMICAL (IN CHEMICO) ASSAYS 244
12.2.3 IN VITRO 2D ASSAYS 245
12.2.4 ORGANOTYPIC MODELS 246
12.3 GENOTOXICITY AS A CASE STUDY 246
12.3.1 MATERIALS AND METHODS 248
12.3.1.1 EPISKIN 248
12.3.1.2 RHE 249
12.3.1.3 TK6 CELLS 249
12.3.1.4 EPISKIN + TK6 CELLS COCULTURE 250
12.3.2 CHEMICALS 250
12.3.3 TREATMENT SCHEDULES 250
12.3.3.1 EPISKIN + TK6 CELLS COCULTURE 250
12.3.3.2 RHE 254
12.3.3.3 MICRONUCLEUS ASSAY 255
12.3.3.4 IN VITRO COMET ASSAY PROTOCOL 256
12.3.3.5 STATISTICAL ANALYSIS 257
12.3.4 RESULTS 257
12.3.4.1 IN VITRO AND IN VIVO GENOTOXINS 257
12.3.4.2 NON-DNA-REACTIVE CHEMICALS (INCLUDING NONGENOTOXIC CARCINOGENS)
THAT GIVE NEGATIVE RESULTS IN THE IN VITRO MAMMALIAN
CELL GENOTOXICITY TESTS 263
12.3.4.3 NON-DNA-REACTIVE CHEMICALS (INCLUDING NONGENOTOXIC CARCINOGENS)
THAT HAVE BEEN REPORTED TO INDUCE POSITIVE RESULTS IN VITRO (CA, MLA/
TK), OFTEN AT HIGH CONCENTRATIONS OR AT HIGH LEVELS OF CYTOTOXICITY 264
12.3.4.4 DISCUSSION 265
12.3.4.5 CONCLUSIONS 267
12.3.4.6 RELATED INITIATIVES 268
12.4 THE WAY FORWARD: COMBINING IN SILICO AND IN VITRO TOOLS 268
ABBREVIATIONS 269
REFERENCES 270
XII
| CONTENTS
13 USING PLURIPOTENT STEM CELLS AND THEIR PROGENY AS AN IN VITRO
MODEL TO ASSESS (DEVELOPMENTAL) NEUROTOXICITY 279
LISA HOELTING,
MARCEL LEIST, AND
LUC STOPPINI
13.1 INTRODUCTION 279
13.2 NEURODEVELOPMENT IN VIVO 281
13.3 MAIN PRINCIPLE OF IN VITRO TEST SYSTEMS TO MODEL DNT 283
13.4 REQUIREMENTS OF AN IN VITRO TEST SYSTEM FOR DNT/NT 284
13.5 MODELING OF DISEASE AND TOXICANT-INDUCED DAMAGE 291
13.6 USING STEM CELLS TO ASSESS (DEVELOPMENTAL) NEUROTOXICITY 296
13.6.1 PROLIFERATION AND CELL DEATH 296
13.6.2 DIFFERENTIATION 297
13.6.3 MIGRATION 298
13.6.4 NEURITOGENESIS 299
13.6.5 SYNAPTOGENESIS AND NEURONAL EXCITABILITY 300
13.6.6 MYELINATION 302
13.6.7 NEUROINFLAMMATION 302
13.7 LIMITATIONS 303
REFERENCES 304
14 STEM CELL-BASED METHODS FOR IDENTIFYING DEVELOPMENTAL
TOXICITY POTENTIAL 321
JESSICA A. PALMER, ROBERT
E. BURRIER, LAURA
A. EGNASH, AND
ELIZABETH L.R.
DONLEY
14.1 INTRODUCTION 321
14.2 DEVELOPMENTAL TOXICITY SCREENING: PAST AND PRESENT 321
14.2.1 DEFINITION AND SCOPE OF THE PROBLEM 321
14.2.2 HISTORICAL STRATEGIES AND THE NEED FOR NEW HUMAN-BASED
MODELS 323
14.3 PJURIPOTENT STEM CELLS 324
14.3.1 DEFINITION 324
14.3.2 ETHICAL CONSIDERATIONS 325
14.4 METABOLOMICS 326
14.4.1 DEFINITION 326
14.4.2 METHODS 326
14.4.3 UNTARGETED VERSUS TARGETED METABOLOMIC APPROACHES 328
14.4.4 METABOLOMICS IN TOXICOLOGY 329
14.5 STEM CELL-BASED IN VITRO SCREENS FOR DEVELOPMENTAL TOXICITY
TESTING 331
14.5.1 MOUSE EMBRYONIC STEM CELL TEST 331
14.5.2 HUMAN EMBRYONIC STEM CELL-BASED DEVELOPMENTAL TOXICITY TESTS 332
14.5.3 COMBINING HUMAN EMBRYONIC STEM CELLS AND METABOLOMICS:
A POWERFUL TOOL FOR DEVELOPMENTAL TOXICITY TESTING 333
14.5.4 DRAWBACKS OF IN VITRO MODELS 337
14.6 SUMMARY 338
REFERENCES 339
CONTENTS | XIII
15 IMMUNOGENICITY OF PROTEIN THERAPEUTICS: RISK ASSESSMENT
AND RISK MITIGATION 347
HARALD KROPSHOFER
15.1 INTRODUCTION 347
15.2 THE CENTRAL ROLE OF CD4
+
T CELLS 349
15.3 GENERATION OF T-CELL EPITOPES 350
15.3.1 HLA RESTRICTION 350
15.3.2 T-CELL EPITOPES CONTROLLING IMMUNOGENICITY 352
15.4 TOLERANCE TO THERAPEUTIC DRUGS 352
15.5 TOOL SET FOR IMMUNOGENICITY RISK ASSESSMENT 353
15.5.1 EPITOPE DETERMINATION 353
15.5.1.1 IN SILICO SCREENING 353
15.5.1.2 PEPTIDE ELUTION 354
15.5.2 HLA BINDING ASSAYS 354
15.5.2.1 COMPETITION BINDING ASSAY 354
15.5.2.2 REAL-TIME KINETIC MEASUREMENTS 355
15.5.3 T-CELL ACTIVATION ASSAYS 355
15.5.3.1 CYTOKINE RELEASE 355
15.5.3.2 T-CELL PROLIFERATION 356
15.5.3.3 TETRAMERS 356
15.5.3.4 NAIVE T-CELL ASSAY 356
15.5.3.5 T-CELL STIMULATION BY WHOLE THERAPEUTIC PROTEINS 356
15.5.3.6 T-CELL RESPONSES IN ARTIFICIAL LYMPH NODES 356
15.5.4 MOUSE MODELS 357
15.5.4.1 HLA TRANSGENIC MICE 357
15.5.4.2 HUMANIZED MOUSE MODELS 357
15.5.5 CASE STUDIES 358
15.5.5.1 TRANSLATION OF IN SILICO AND IN VITRO DATA INTO CLINICAL
CONTEXT 358
15.5.5.2 LINK BETWEEN HLA HAPLOTYPE AND IMMUNOGENICITY: IN VIVO
VERSUS IN VITRO 359
15.6 IMMUNOGENICITY RISK MITIGATION 359
15.6.1 DEIMMUNIZATION 360
15.6.2 TOLERIZATION 360
15.6.3 CLINICAL CONTROL OF IMMUNOGENICITY RISK FACTORS 361
15.7 THE INTEGRATED STRATEGY OF RISK MINIMIZATION 361
15.8 SUMMARY 363
REFERENCES 364
16 REGULATORY ASPECTS 369
BEATRIZ SILVA
LIMA
16.1 THE HISTORY OF MEDICINES REGULATIONS IN BRIEF 369
16.1.1 UNITED STATES OF AMERICA 369
16.1.2 EUROPE 370
16.1.3 THE INTERNATIONAL CONFERENCE ON HARMONISATION 371
XIV
| CONTENTS
16.2 IMPACT ON DRUG SUCCESS OF THE CURRENT ICH NONCLINICAL TESTING
PARADIGM 373
16.3 ACTIONS TAKEN FOR INCREASING THE DRUG DEVELOPMENT SUCCESS 374
16.4 INNOVATIVE DRUGS: IMPACT ON NONCLINICAL DEVELOPMENT
STRATEGIES 376
16.4.1 BIOPHARMACEUTICALS 376
16.4.2 ADVANCED THERAPY MEDICINAL PRODUCTS 377
16.4.3 NANOPHARMACEUTICALS 379
16.4.4 BIOSIMILAR MEDICINAL PRODUCTS 380
16.4.5 INNOVATIVE SMALL CHEMICAL ENTITIES 380
16.5 ENVISAGING A PARADIGM CHANGE 381
16.5.1 THE PRESENT 381
16.5.2 THE BASIS FOR A PARADIGM CHANGE 382
16.5.3 VISION OF A RENEWED PARADIGM 385
16.6 REGULATORY ACTIONS NEEDED TO SHIFT THE ANIMAL-BASED PARADIGM 386
REFERENCES 388
INDEX
391 |
| any_adam_object | 1 |
| author2 | Pfannkuch, Friedlieb |
| author2_role | edt |
| author2_variant | f p fp |
| author_facet | Pfannkuch, Friedlieb |
| building | Verbundindex |
| bvnumber | BV042165369 |
| classification_rvk | VS 5700 VT 5300 |
| ctrlnum | (OCoLC)881386714 (DE-599)DNB1051706858 |
| dewey-full | 615.9 |
| dewey-hundreds | 600 - Technology (Applied sciences) |
| dewey-ones | 615 - Pharmacology and therapeutics |
| dewey-raw | 615.9 |
| dewey-search | 615.9 |
| dewey-sort | 3615.9 |
| dewey-tens | 610 - Medicine and health |
| discipline | Chemie / Pharmazie Medizin |
| format | Book |
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| genre_facet | Aufsatzsammlung |
| id | DE-604.BV042165369 |
| illustrated | Illustrated |
| indexdate | 2024-09-10T01:29:16Z |
| institution | BVB |
| isbn | 9783527336081 9783527674183 |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-027604910 |
| oclc_num | 881386714 |
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| owner_facet | DE-29 DE-20 DE-19 DE-BY-UBM DE-355 DE-BY-UBR |
| physical | XXV, 404 S. graph. Darst. 240 mm x 170 mm |
| publishDate | 2015 |
| publishDateSearch | 2015 |
| publishDateSort | 2015 |
| publisher | Wiley-VCH |
| record_format | marc |
| series | Methods and principles in medicinal chemistry |
| series2 | Methods and principles in medicinal chemistry |
| spelling | Predictive toxicology from vision to reality ed. by Friedlieb Pfannkuch ... Weinheim Wiley-VCH 2015 XXV, 404 S. graph. Darst. 240 mm x 170 mm txt rdacontent n rdamedia nc rdacarrier Methods and principles in medicinal chemistry 64 Toxikologie (DE-588)4060538-3 gnd rswk-swf Wirkstoff (DE-588)4066383-8 gnd rswk-swf (DE-588)4143413-4 Aufsatzsammlung gnd-content Wirkstoff (DE-588)4066383-8 s Toxikologie (DE-588)4060538-3 s DE-604 Pfannkuch, Friedlieb edt Erscheint auch als Online-Ausgabe, EPUB 978-3-527-67420-6 Erscheint auch als Online-Ausgabe, MOBI 978-3-527-67421-3 Erscheint auch als Online-Ausgabe, PDF 978-3-527-67419-0 Methods and principles in medicinal chemistry 64 (DE-604)BV035418617 64 X:MVB text/html http://deposit.dnb.de/cgi-bin/dokserv?id=4680903&prov=M&dok_var=1&dok_ext=htm Inhaltstext DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=027604910&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Predictive toxicology from vision to reality Methods and principles in medicinal chemistry Toxikologie (DE-588)4060538-3 gnd Wirkstoff (DE-588)4066383-8 gnd |
| subject_GND | (DE-588)4060538-3 (DE-588)4066383-8 (DE-588)4143413-4 |
| title | Predictive toxicology from vision to reality |
| title_auth | Predictive toxicology from vision to reality |
| title_exact_search | Predictive toxicology from vision to reality |
| title_full | Predictive toxicology from vision to reality ed. by Friedlieb Pfannkuch ... |
| title_fullStr | Predictive toxicology from vision to reality ed. by Friedlieb Pfannkuch ... |
| title_full_unstemmed | Predictive toxicology from vision to reality ed. by Friedlieb Pfannkuch ... |
| title_short | Predictive toxicology |
| title_sort | predictive toxicology from vision to reality |
| title_sub | from vision to reality |
| topic | Toxikologie (DE-588)4060538-3 gnd Wirkstoff (DE-588)4066383-8 gnd |
| topic_facet | Toxikologie Wirkstoff Aufsatzsammlung |
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| volume_link | (DE-604)BV035418617 |
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