Population pharmacokinetic modelling and simulation of monoclonal antibodies including the impact of immunogenicity and importance of study and analysis design factors:
Gespeichert in:
| 1. Verfasser: | |
|---|---|
| Format: | Abschlussarbeit Buch |
| Sprache: | English |
| Veröffentlicht: |
Aachen
Shaker
2014
|
| Ausgabe: | 1. Aufl. |
| Schriftenreihe: | Berichte aus der Pharmazie
|
| Schlagworte: | |
| Online-Zugang: | Inhaltsverzeichnis |
| Beschreibung: | XI, 242 S. graph. Darst. 210 mm x 148 mm, 390 g |
| ISBN: | 9783844026504 |
Internformat
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| 245 | 1 | 0 | |a Population pharmacokinetic modelling and simulation of monoclonal antibodies including the impact of immunogenicity and importance of study and analysis design factors |c Ronald Niebecker |
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Datensatz im Suchindex
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| adam_text | CONTENTS
ABBREVIATIONS AND SYMBOLS VII
1 INTRODUCTION 1
1.1 PHARMACOMETRICS - MODELLING AND SIMULATION 1
1.1.1 OVERVIEW AND BACKGROUND 1
1.1.2 POPULATION ANALYSIS USING THE NONLINEAR MIXED-EFFECTS APPROACH 4
1.1.3 SIMULATION-BASED ANALYSIS 5
1.2 MONOCLONAL ANTIBODIES 5
1.2.1 MONOCLONAL ANTIBODY STRUCTURE AND HISTORY 5
1.2.2 PHARMACOKINETICS OF MONOCLONAL ANTIBODIES 6
1.2.2.1 ABSORPTION 6
1.2.2.2 DISTRIBUTION 7
1.2.2.3 METABOLISM AND EXCRETION 8
1.2.2.4 POPULATION PHARMACOKINETICS OF MONOCLONAL ANTIBODIES 8
1.2.3 PHARMACODYNAMICS OF MONOCLONAL ANTIBODIES 9
1.2.4 SAFETY OF MONOCLONAL ANTIBODIES 10
1.2.5 SIBROTUZUMAB 10
1.3 TMMUNOGENICITY 12
1.3.1 CAUSES OF IMMUNOGENICITY 12
1.3.2 ANTI-DRUG ANTIBODY TERMINOLOGY AND CLASSIFICATION 12
1.3.3 FACTORS INFLUENCING THE IMMUNE RESPONSE 13
1.3.4 INCIDENCE OF ANTI-DRUG ANTIBODY DEVELOPMENT 14
1.3.5 POTENTIAL IMPACT OF ANTI-DRUG ANTIBODIES 14
1.3.6 MANAGEMENT OF IMMUNOGENICITY 15
1.3.7 IMMUNOGENICITY BIOANALYTICS 17
1.3.7.1 CAUSES OF CHALLENGES IN IMMUNOGENICITY BIOANALYTICS 17
1.3.7.2 RISK-BASED APPROACHES TO IMMUNOGENICITY ASSESSMENT 18
1.3.7.3 RECOMMENDATIONS FOR ASSAY DEVELOPMENT AND VALIDATION .... 19
1.3.7.4 OVERVIEW OF METHODS IN IMMUNOGENICITY BIOANALYTICS 19
1.3.8 IMMUNOGENICITY IN PHARMACOMETRICS 21
1.4 DESIGN FACTORS OF CLINICAL TRIALS AND EVALUATION FOR IDENTIFIABILITY
OF PHARMACOKI
NETIC PARAMETERS 22
1.4.1 STUDY AND ANALYSIS DESIGN FACTORS 22
1.4.2 APPROACHES TO INVESTIGATE IMPORTANCE OF STUDY DESIGN FACTORS 23
1.5 OBJECTIVES 23
HTTP://D-NB.INFO/1047913208
CONTENTS
2 METHODS AND STUDIES 25
2.1 POPULATION ANALYSIS USING THE NLME APPROACH 25
2.1.1 NONLINEAR MIXED-EFFECTS MODELLING 25
2.1.1.1 NONMEM 25
2.1.1.2 MODEL COMPONENTS 25
2.1.1.3 ESTIMATION METHODS AND FURTHER TECHNICAL SPECIFICATIONS .... 28
2.1.2 MODEL DEVELOPMENT 31
2.1.2.1 STRUCTURAL SUBMODEL 31
2.1.2.2 STOCHASTICAL SUBMODEL 31
2.1.2.3 COVARIATE SUBMODEL 34
2.1.3 MODEL SELECTION 39
2.1.4 MODEL EVALUATION 40
2.1.4.1 EXTERNAL EVALUATION 40
2.1.4.2 INTERNAL EVALUATION 41
2.2 SIMULATIONS 42
2.2.1 DETERMINISTIC SIMULATIONS 43
2.2.2 STOCHASTIC SIMULATIONS 43
2.2.3 SIMULATION-BASED ANALYSES 43
2.3 EXPERIMENTAL DESIGN/CLINICAL STUDIES 44
2.3.1 STUDY OBJECTIVES 44
2.3.2 STUDY DESIGN 44
2.3.2.1 STUDY POPULATION 44
2.3.2.2 STUDY TREATMENT 46
2.3.2.3 SAMPLING OF SIBROTUZUMAB 46
2.3.2.4 SAMPLING FOR IMMUNE RESPONSE 46
2.3.3 BIOANALYTICAL METHODS 46
2.3.3.1 SIBROTUZUMAB BIOANALYTICS 47
2.3.3.2 IMMUNE RESPONSE ANALYTICS 48
2.4 DATA PREPARATION 49
2.4.1 DATA SOURCES AND DATASET, MODIFICATION 49
2.4.2 DATA CHECKOUT AND EXPLORATORY DATA ANALYSIS 49
2.4.3 EXPLORATORY GRAPHICAL ANALYSIS 49
2.4.4 MISSING DATA 49
2.5 MODELLING AND SIMULATION STRATEGIES 50
2.5.1 PROJECT I: SIBROTUZUMAB POPULATION PHARMACOKINETICS PRIOR TO
IMMUNE
RESPONSE 50
2.5.1.1 OBJECTIVES AND INITIAL SITUATION 50
2.5.1.2 INVESTIGATIONS CONCERNING THE STRUCTURAL SUBMODEL 51
2.5.1.3 INVESTIGATIONS CONCERNING THE STOCHASTICAL SUBMODEL 52
2.5.1.4 INVESTIGATIONS CONCERNING THE COVARIATE SUBMODEL 52
2.5.1.5 MODEL EVALUATION INCLUDING SIMULATIONS 53
2.5.2 PROJECT II: MODELLING OF AN IMMUNE RESPONSE SURROGATE 54
2.5.2.1 OBJECTIVES 54
2.5.2.2 INVESTIGATIONS CONCERNING THE DIFFERENT SUBMODELS 54
2.5.2.3 MODEL EVALUATION INCLUDING SIMULATIONS 55
CONTENTS
2.5.3 PROJECT III: MODELLING OF THE ANTI-DRUG ANTIBODY INFLUENCE ON THE
POPULA
TION PHARMACOKINETICS OF SIBROTUZUMAB 55
2.5.3.1 OBJECTIVES AND INITIAL CONSIDERATIONS 55
2.5.3.2 INVESTIGATIONS CONCERNING THE DIFFERENT SUBMODELS 56
2.5.3.3 MODEL EVALUATION INCLUDING SIMULATIONS 57
2.5.4 PROJECT IV: SIMULATION-BASED ANALYSIS CONCERNING THE IMPORTANCE OF
DE
SIGN FACTORS FOR PARAMETER IDENTIFIABILITY 58
2.5.4.1 OBJECTIVES 58
2.5.4.2 TECHNICAL IMPLEMENTATION AND WORKFLOW EVALUATION 58
2.5.4.3 WORKFLOW APPLICATION 61
2.G STATISTICS 64
2.6.1 DESCRIPTIVE STATISTICS 64
2.6.2 INFERENTIAL STATISTICS 64
2.7 SOFTWARE 65
3 RESULTS 67
3.1 RESULTS RELEVANT TO PROJECTS I*III 67
3.1.1 PATIENT CHARACTERISTICS 67
3.1.2 DRUG ADMINISTRATIONS 68
3.1.3 IMMUNOGENICITY 68
3.1.4 THERAPEUTIC MONOCLONAL ANTIBODY MEASUREMENTS 69
3.1.5 ANTI-DRUG ANTIBODY MEASUREMENTS 71
3.1.6 DATASETS FOR ANALYSIS 71
3.2 PROJECT I: SIBROTUZUMAB POPULATION PHARMACOKINETICS 72
3.2.1 OBSERVATIONS: SIBROTUZUMAB CONCENTRATION-TIME PROFILES 72
3.2.2 MODEL DEVELOPMENT 72
3.2.2.1 STRUCTURAL SUBMODEL 72
3.2.2.2 STOCHASTICAL SUBMODEL 74
3.2.2.3 COVARIATE SUBMODEL 75
3.2.3 FINAL MODELS 81
3.2.4 MODEL EVALUATION 84
3.2.4.1 BASIC INTERNAL MODEL EVALUATION 84
3.2.4.2 CASE-DELETION DIAGNOSTICS 84
3.2.4.3 ROBUSTNESS OF CONVERGENCE 87
3.2.4.4 BOOTSTRAP ANALYSIS 87
3.2.4.5 COMPARISON OF CONFIDENCE INTERVALS 89
3.2.4.6 VISUAL PREDICTIVE CHECK ANALYSIS 93
3.2.4.7 SUMMARY OF MODEL EVALUATION RESULTS 93
3.2.5 SIMULATIONS 97
3.2.5.1 COMPARISON OF CLC MODEL AND PLC MODEL 97
3.2.5.2 COMPARISON OF CLC MODEL WITH THE PREVIOUS MODEL FOR SIBRO
TUZUMAB PHARMACOKINETICS 98
3.2.5.3 SIMULATIONS CONCERNING THE IMPACT OF BODY SIZE 100
3.3 PROJECT II: IMMUNE RESPONSE SURROGATE MODELLING 106
3.3.1 OBSERVATIONS: SURFACE PLASMON RESONANCE ASSAY SIGNAL-TIME PROFILES
. . . 106
III
CONTENTS
3.3.2 MODEL DEVELOPMENT 106
3.3.2.1 STRUCTURAL SUBMODEL 106
3.3.2.2 STOCHASTICAL SUBMODEL 109
3.3.2.3 COVARIATE SUBMODEL 109
3.3.3 FINAL MODELS 109
3.3.4 MODEL EVALUATION INCLUDING SIMULATIONS 112
3.3.4.1 BASIC INTERNAL MODEL EVALUATION 112
3.3.4.2 SIMULATIONS 116
3.3.4.3 ADVANCED INTERNAL MODEL EVALUATION 117
3.4 PROJECT III: ADA INFLUENCE ON SIBROTUZUMAB PHARMACOKINETICS 120
3.4.1 OBSERVATIONS 120
3.4.2 MODEL DEVELOPMENT FOR DATASET I 123
3.4.2.1 APPLICATION OF THE UNALTERED CLC MODEL 124
3.4.2.2 STRUCTURAL SUBMODEL 128
3.4.2.3 STOCHASTICAL SUBMODEL 128
3.4.2.4 COVARIATE SUBMODEL 129
3.4.3 FINAL MODELS FOR DATASET I 130
3.4.4 MODEL DEVELOPMENT AND FINAL MODELS FOR DATASET II 132
3.4.5 MODEL EVALUATION 134
3.4.5.1 BASIC INTERNAL MODEL EVALUATION 134
3.4.5.2 ADVANCED INTERNAL MODEL EVALUATION 137
3.4.6 SIMULATIONS 141
3.5 PROJECT IV: DESIGN FACTORS/SIMULATION-BASED ANALYSIS 144
3.5.1 WORKFLOW IMPLEMENTATION . . 144
3.5.2 WORKFLOW EVALUATION 146
3.5.3 WORKFLOW APPLICATION 146
3.5.3.1 SIMULATION STUDY I 147
3.5.3.2 SIMULATION STUDY II 148
4 DISCUSSION 157
4.1 POPULATION PHARMACOKINETIC ANALYSIS OF MONOCLONAL ANTIBODIES 157
4.1.1 DATA BASIS 157
4.1.2 POPULATION PHARMACOKINETIC MODEL AND PARAMETERS 158
4.1.2.1 STRUCTURAL SUBMODEL 158
4.1.2.2 STOCHASTICAL SUBMODEL 165
4.1.2.3 COVARIATE SUBMODEL 168
4.1.3 IMPACT OF ESTIMATION METHOD 174
4.1.4 FINAL ASSESSMENT 175
4.2 IMMUNOGENICITY IN MONOCLONAL ANTIBODY PHARMACOKINETICS 176
4.2.1 CLINICAL FINDINGS CONCERNING IMMUNOGENICITY 176
4.2.2 MODELLING OF AN IMMUNE RESPONSE SURROGATE 177
4.2.2.1 DATA BASIS AND MODELLING APPROACH 177
4.2.2.2 STRUCTURAL SUBMODEL 179
4.2.2.3 COVARIATE SUBMODEL 180
4.2.2.4 SHORT SUMMARY 180
CONTENTS
4.2.3 IMMUNOGENICITY INFLUENCING MONOCLONAL ANTIBODY PHARMACOKINETICS .
. . 180
4.2.3.1 DATA BASIS AND MODELLING APPROACH 180
4.2.3.2 STRUCTURAL SUBMODEL 182
4.2.3.3 STOCHASTICAL SUBMODEL 183
4.2.3.4 COVARIATE SUBMODEL 184
4.2.3.5 MODELLING BASED ON DIFFERENT DATASETS 184
4.2.4 ALTERNATIVE WAYS OF HANDLING IMIIIUNOGENICITY AND FINAL ASSESSMENT
. . . 185
4.3 DESIGN FACTORS IN MONOCLONAL ANTIBODY PHARMACOKINETICS 189
4.3.1 WORKFLOW SETUP AND EVALUATION 189
4.3.2 STUDY DESIGN INVESTIGATIONS 189
4.3.2.1 PARAMETERS OF THE INPUT-OUTPUT MODEL AND SIMULATION STUDY SET
TINGS 190
4.3.2.2 INFLUENCE OF STUDY DESIGN AND ANALYSIS DESIGN CHARACTERISTICS ON
PARAMETER IDENTIFIABILITY 191
5 CONCLUSION AND PERSPECTIVES 195
6 ABSTRACT ~ 199
7 ZUSAMMENFASSUNG 201
8 BIBLIOGRAPHY 203
9 PUBLICATIONS 223
10 APPENDIX 225
10.1 TABLES 225
10.2 FIGURES 231
11 ACKNOWLEDGEMENTS 241
V
|
| any_adam_object | 1 |
| author | Niebecker, Ronald |
| author_facet | Niebecker, Ronald |
| author_role | aut |
| author_sort | Niebecker, Ronald |
| author_variant | r n rn |
| building | Verbundindex |
| bvnumber | BV041846579 |
| classification_rvk | XD 3190 |
| ctrlnum | (OCoLC)915459625 (DE-599)DNB1047913208 |
| dewey-full | 616.0798 |
| dewey-hundreds | 600 - Technology (Applied sciences) |
| dewey-ones | 616 - Diseases |
| dewey-raw | 616.0798 |
| dewey-search | 616.0798 |
| dewey-sort | 3616.0798 |
| dewey-tens | 610 - Medicine and health |
| discipline | Medizin |
| edition | 1. Aufl. |
| format | Thesis Book |
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| record_format | marc |
| series2 | Berichte aus der Pharmazie |
| spelling | Niebecker, Ronald Verfasser aut Population pharmacokinetic modelling and simulation of monoclonal antibodies including the impact of immunogenicity and importance of study and analysis design factors Ronald Niebecker 1. Aufl. Aachen Shaker 2014 XI, 242 S. graph. Darst. 210 mm x 148 mm, 390 g txt rdacontent n rdamedia nc rdacarrier Berichte aus der Pharmazie Zugl.: Berlin, Freie Univ., Diss., 2013 Computersimulation (DE-588)4148259-1 gnd rswk-swf Immunogenität (DE-588)4278029-9 gnd rswk-swf Monoklonaler Antikörper (DE-588)4040094-3 gnd rswk-swf Pharmakokinetik (DE-588)4115557-9 gnd rswk-swf Biologika (DE-588)7689632-8 gnd rswk-swf (DE-588)4113937-9 Hochschulschrift gnd-content Monoklonaler Antikörper (DE-588)4040094-3 s Biologika (DE-588)7689632-8 s Pharmakokinetik (DE-588)4115557-9 s Immunogenität (DE-588)4278029-9 s Computersimulation (DE-588)4148259-1 s DE-604 DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=027291129&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Niebecker, Ronald Population pharmacokinetic modelling and simulation of monoclonal antibodies including the impact of immunogenicity and importance of study and analysis design factors Computersimulation (DE-588)4148259-1 gnd Immunogenität (DE-588)4278029-9 gnd Monoklonaler Antikörper (DE-588)4040094-3 gnd Pharmakokinetik (DE-588)4115557-9 gnd Biologika (DE-588)7689632-8 gnd |
| subject_GND | (DE-588)4148259-1 (DE-588)4278029-9 (DE-588)4040094-3 (DE-588)4115557-9 (DE-588)7689632-8 (DE-588)4113937-9 |
| title | Population pharmacokinetic modelling and simulation of monoclonal antibodies including the impact of immunogenicity and importance of study and analysis design factors |
| title_auth | Population pharmacokinetic modelling and simulation of monoclonal antibodies including the impact of immunogenicity and importance of study and analysis design factors |
| title_exact_search | Population pharmacokinetic modelling and simulation of monoclonal antibodies including the impact of immunogenicity and importance of study and analysis design factors |
| title_full | Population pharmacokinetic modelling and simulation of monoclonal antibodies including the impact of immunogenicity and importance of study and analysis design factors Ronald Niebecker |
| title_fullStr | Population pharmacokinetic modelling and simulation of monoclonal antibodies including the impact of immunogenicity and importance of study and analysis design factors Ronald Niebecker |
| title_full_unstemmed | Population pharmacokinetic modelling and simulation of monoclonal antibodies including the impact of immunogenicity and importance of study and analysis design factors Ronald Niebecker |
| title_short | Population pharmacokinetic modelling and simulation of monoclonal antibodies including the impact of immunogenicity and importance of study and analysis design factors |
| title_sort | population pharmacokinetic modelling and simulation of monoclonal antibodies including the impact of immunogenicity and importance of study and analysis design factors |
| topic | Computersimulation (DE-588)4148259-1 gnd Immunogenität (DE-588)4278029-9 gnd Monoklonaler Antikörper (DE-588)4040094-3 gnd Pharmakokinetik (DE-588)4115557-9 gnd Biologika (DE-588)7689632-8 gnd |
| topic_facet | Computersimulation Immunogenität Monoklonaler Antikörper Pharmakokinetik Biologika Hochschulschrift |
| url | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=027291129&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| work_keys_str_mv | AT niebeckerronald populationpharmacokineticmodellingandsimulationofmonoclonalantibodiesincludingtheimpactofimmunogenicityandimportanceofstudyandanalysisdesignfactors |