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Physiologically-Based Pharmacokinetic (PBPK) Modeling and Simulations: Principles, Methods, and Applications in the Pharmaceutical Industry ist das einzige Buch seiner Art, das sich an die schnell wachsende Gemeinschaft der PBPK-Anwender richtet und in klaren, prägnanten Worten die Grundlagen darstellt. Durch die Verbindung von Theorie und Praxis wird in diesem Werk das unglaubliche Potenzial der PBPK-Modellierung für die Verbesserung der Entdeckung und Entwicklung von Arzneimitteln betrachtet. In der neuen Ausgabe wird der Schwerpunkt stärker auf Anwendungen und relevante Fallstudien gelegt. Außerdem gibt es eine begleitende Website mit Datensätzen, die viele der wichtigsten Entwicklungen im Bereich der PBPK-Modellierung und -Simulation seit der Veröffentlichung der ersten Ausgabe im Jahr 2012 abbilden.
Physiologically-Based Pharmacokinetic (PBPK) Modeling and Simulations: Principles, Methods, and Applications in the Pharmaceutical Industry ist das einzige Buch seiner Art, das sich an die schnell wachsende Gemeinschaft der PBPK-Anwender richtet und in klaren, prägnanten Worten die Grundlagen darstellt. Durch die Verbindung von Theorie und Praxis wird in diesem Werk das unglaubliche Potenzial der PBPK-Modellierung für die Verbesserung der Entdeckung und Entwicklung von Arzneimitteln betrachtet. In der neuen Ausgabe wird der Schwerpunkt stärker auf Anwendungen und relevante Fallstudien gelegt. Außerdem gibt es eine begleitende Website mit Datensätzen, die viele der wichtigsten Entwicklungen im Bereich der PBPK-Modellierung und -Simulation seit der Veröffentlichung der ersten Ausgabe im Jahr 2012 abbilden.
Über den Autor
Sheila Annie Peters, PhD, is Head of Translational Quantitative Pharmacology at Merck Healthcare, Darmstadt, Germany. Previously, she was an Associate Principal Scientist for Discovery DMPK and Bioanalytical Chemistry at AstraZeneca and Principal Scientist at Cyprotex Discovery. She has lectured at the Regional Engineering College (Trichy, India) and University of Madras and Pondicherry University.
Inhaltsverzeichnis
Preface xix
Acknowledgements xxi
About the companion xxiii
Section I. Principles, Methods, andBackground Information 1
1 A Review of Pharmacokinetic and Pharmacodynamic Principles 3
1.1 Introduction 4
1.2 Pharmacokinetic Principles 4
1.2.1 Routes of Drug Administration 4
1.2.2 Intravenous Bolus 4
1.2.3 Plasma Protein Binding and Blood-Plasma Ratio 9
1.2.4 Hepatic, Renal, and Biliary Clearances 12
1.2.5 Extravascular (Subcutaneous, Intramuscular, and Per Oral) Absorption 16
1.2.6 Absorption from Solid Dosage Forms 20
1.2.7 Role of Transporters in ADME 22
1.2.8 Linear and Non-Linear Pharmacokinetics 24
1.2.9 Intravenous Infusion, Repeated Dosing, Steady State Kinetics, and Accumulation 25
1.2.10 Active Metabolite and Prodrug Kinetics 28
1.3 Pharmacokinetic Variability 32
1.4 Pharmacokinetics Optimization in Drug Discovery 34
1.5 Pharmacodynamic Principles 34
1.5.1 Pharmacological Targets and Drug Action 35
1.5.2 Functional Adaptation Processes 39
1.5.3 Biomarkers, Surrogate Endpoints, and Clinical Endpoints 41
Keywords 47
References 48
2 A Review of Drug-Drug Interactions 51
2.1 Introduction 51
2.2 Drug Interactions Mediated by Enzymes and Transporters at Various Sites 54
2.3 Factors Affecting DDI 54
2.4 In Vitro Methods to Evaluate Drug-Drug Interactions 56
2.4.1 Candidate Drug as a Potential Perpetrator 57
2.4.2 Candidate Drug as a Potential Victim of Inhibition 58
2.5 Sources of Uncertainty 59
2.6 Therapeutic Protein-Drug Interaction 59
References 61
3 Modeling Pharmacokinetics, Pharmacodynamics, And Drug Interactions 65
3.1 Introduction 66
3.2 Modeling Pharmacokinetics 66
3.2.1 Compartmental Modeling of Linear and Nonlinear Pharmacokinetics (Enzyme and/or Transporter Capacity Limitation as Well as Target-Mediated Drug Disposition) 67
3.2.2 Population Pharmacokinetics 76
3.3 Pharmacokinetics/Pharmacodynamics and PK/Efficacy (Exposure/ Response) Modeling 80
3.3.1 PK/PD Models for Direct Effect: Sigmoid Emax Model 84
3.3.2 PK/PD Models for Direct Effect: Classical Receptor Theory 86
3.3.3 PK/PD Models Accommodating Delayed Pharmacological Response 89
3.3.4 PK/PD Models Accommodating Functional Adaptation Leading to Nonlinearity in Pharmacological Response with Respect to Time 96
3.3.5 PK/Efficacy Modeling 97
3.3.6 Translation of PK/PD and PK/Efficacy Modeling to Human 100
3.3.7 Average, Minimum, and Maximum Steady-State Concentrations 104
3.3.8 Estimation of Biologically Effective Dose in Human 107
3.3.9 Therapeutic Window 109
3.3.10 Static Models for Drug Interactions 109
3.4 Physiologically Based Pharmacokinetic (PBPK) Modeling and Its Integration with Pharmacodynamics and Efficacy Models 112
3.4.1 PK Modeling Compartmental vs PBPK 112
3.4.2 PK Variability: Population PK (popPK) Modeling vs PBPK 114
3.4.3 Integration of PBPK with PD, Quantitative Systems Pharmacology (QSP) Models or Quantitative Systems Toxicologyand Safety (QSTS) 114
3.4.4 PBPK Models to Evaluate Drug-Drug Interactions 115
3.4.5 DDI Risk Assessment with PBPK vs Static Models 118
Keywords 123
References 125
4 Physiological Model For Absorption 129
4.1 Introduction 130
4.2 Drug Absorption and Gut Bioavailability 130
4.2.1 Solubility and Dissolution Rate 130
4.2.2 Permeability: Transcellular, Paracellular, and Carrier-Mediated Pathways 136
4.2.3 Barriers to Membrane Transport - Luminal Degradation, Efflux, and Gut Metabolism 138
4.3 Factors Affecting Drug Absorption and Gut Bioavailability 140
4.3.1 Physiological Factors Affecting Oral Drug Absorption and Species Differences in Physiology 140
4.3.2 Compound-Dependent Factors 144
4.3.3 Formulation-Dependent Factors 144
4.4 In Silico Predictions of Passive Permeability and Solubility 147
4.4.1 In Silico Models for Permeability 147
4.4.2 In Silico Models for Solubility 147
4.5 Measurement of Permeability, Solubility, Luminal Stability, Efflux, Intestinal Metabolism 148
4.5.1 In Vitro, In Situ, and In Vivo Models for Effective Permeability 148
4.5.2 Measurement of Thermodynamic or Equilibrium Solubility 153
4.5.3 Luminal Stability 154
4.5.4 Efflux 154
4.5.5 In Vitro Models for Gut Metabolism and Estimation of Fraction Escaping Gut Metabolism 155
4.6 Absorption Modeling 156
Keywords 162
References 163
5 Physiological Model For Distribution 169
5.1 Introduction 170
5.2 Factors Affecting Tissue Distribution of Xenobiotics 170
5.2.1 Physiological Factors and Species Differences in Physiology 171
5.2.2 Compound-Dependent Factors 176
5.3 In Silico Models of Tissue Partition Coefficients 176
5.4 Measurement of Parameters Representing the Rate and Extent of Tissue Distribution 181
5.4.1 Assessment of Rate and Extent of Brain Penetration 181
5.5 Physiological Model for Drug Distribution 186
5.6 Drug Concentrations at the Site of Action 187
Keywords 189
References 189
6 Physiological Models For Drug Metabolism And Excretion 193
6.1 Introduction 193
6.2 Factors Affecting Drug Metabolism and Excretion of Xenobiotics 194
6.3 Models for Hepatobiliary and Renal Excretion 197
6.3.1 In Silico Models 197
6.3.2 In Vitro Models for Hepatic Metabolism 197
6.3.3 In Vitro Models for Transporters 200
6.4 Physiological Models 203
6.4.1 Hepato-Biliary Elimination of Parent Drug and Metabolites 205
6.4.2 Renal Excretion 208
References 211
7 Generic Whole-Body Physiologically Based Pharmacokinetic Modeling 217
7.1 Introduction 217
7.2 Structure of a Generic Physiologically-Based Pharmacokinetic (PBPK) Model 218
7.3 Somatic Compartments 220
7.3.1 Lungs (LU) 220
7.3.2 Arterial Blood (ART) 220
7.3.3 Venous Blood (VEN) 220
7.3.4 Stomach (ST) 220
7.3.5 Gut (GU) 220
7.4 Model Assumptions 221
7.5 PBPK Software 221
References 223
8 Pbpk Modeling Of Biotherapeutics 225
8.1 Introduction 226
8.2 Therapeutic Proteins 226
8.2.1 Peptides and Proteins 226
8.2.2 Antibodies and Antibody-Based Therapies 227
8.3 Pharmacokinetics of Therapeutic Proteins 234
8.3.1 Absorption 234
8.3.2 Renal Elimination 235
8.3.3 Immunogenicity 235
8.3.4 PEGylation 239
8.3.5 Transport by Convective and Transcytotic Extravasation 239
8.3.6 Catabolic Elimination (Proteolysis) 239
8.3.7 FcRn-Mediated Protection of IgGs Against Catabolism in FcRn-Rich Cells 241
8.3.8 Distribution and lymphatic elimination 242
8.3.9 Target-Mediated Drug Disposition and Receptor-Mediated Endocytosis 243
8.4 PBPK Modeling of Monoclonal Antibodies 244
8.4.1 Full PBPK Model for Monoclonal Antibodies 244
8.4.2 Minimal PBPK Model for Monoclonal Antibodies 253
8.5 Applications of PBPK Modeling of Monoclonal Antibodies 253
8.5.1 Pharmacokinetic Scaling 253
8.5.2 PBPK Integration with Pharmacodynamics of Monoclonal Antibodies 255
Keywords 156
References 258
9 Uncertainty And Population Variability 263
9.1 Introduction 264
9.2 Distinguishing Uncertainty and Variability 264
9.3 Sources of Uncertainty in Drug-related Parameters 264
9.4 Sources of Variability in System Parameters 266
9.5 Handling Population Variability 269
9.5.1 A POSTERIORI and A PRIORI Approaches to Handling Population Variability 269
9.5.2 Correlations Between Parameters 271
9.6 Uncertainty and Sensitivity Analysis 272
9.6.1 Local Sensitivity Analysis (One-at-a-time (OAT) and Derivative-based Methods) 272
9.6.2 Parameter Interactions and Global Sensitivity Analysis (GSA) 275
9.6.3 Global Sensitivity Analysis for Correlated Parameters (cGSA) 278
9.6.4 Applications of Sensitivity Analysis for PBPK Models 280
9.6.5 Limitations of Global Sensitivity Analysis 281
9.7 Uncertainty and Population Variability in Clinical Efficacy and Safety 282
Keywords 285
References 285
10 Nonclinical, Clinical, and Model-Informed Drug Development 293
10.1 Introduction: An Overview of Different Phases of Drug Development 294
10.2 Nonclinical Development 295
10.2.1 Preclinical Pharmacology, PK/PD Modeling, and Human Dose Prediction 297
10.2.2 Safety and Toxicology Studies 297
10.2.3 Studies with Radiolabeled Compound 298
10.3 Clinical Pharmacology Studies 302
10.3.1 First-in-Human, Single, and Multiple Ascending Dose Studies 302
10.3.2 Biopharmaceutics - Absolute Oral Bioavailability and Bioequivalence Study 304
10.3.3 Food Effect Study 304
10.3.4 Organ (Hepatic and Renal) Impairment Study 305
10.3.5 Pediatric Assessment 306
10.3.6 Mass Balance Study 307
10.3.7 Drug Interaction Study 307
10.3.8 Pharmacogenomics Study 308
10.3.9 Thorough QT (TQT) and Concentration QT (C-QT) Study 308
10.3.10 Immunogenicity Assays and Comparability Study for Biologics 309
10.3.11 Drug Labelling 309
10.4 Clinical Development in Oncology 310
10.5 Fast Track Routes to Address Unmet Medical Need in the Treatment of Serious Conditions 311
10.6 Model-Informed Drug Development 312
10.7 Physiologically Based Pharmacokinetic Models Complementing Clinical Pharmacology Studies 314
10.8 PBPK in Oncology 315
Regulatory Guidelines 316
References 319
Section II. Applications In The Pharmaceutical Industry 323
11 Overview Of Pbpk Applications 325
11.1 Introduction 325
11.2 PBPK Applications for Internal Decisions 326
11.3 PBPK Applications for Regulatory Filing 328
11.4 PBPK Modeling and Simulations Along the Value Chain 332
References 335
12 Applications Of Hypothesis Generation And Testing With Pbpk Models 337
12.1 Introduction 338
12.2 Hypothesis Generation and Testing with PBPK Models 338
12.2.1 Parameter Estimation from Intravenous Pharmacokinetic Profiles 338
12.2.2 Simulation of Oral PK Profile 341
12.2.3 Sensitivity Analysis 342
12.2.4 Verification of Hypotheses 346
12.2.5 Auto-inhibition of Drug-Metabolizing Enzymes, Uptake and Efflux Transporters 347
12.3 Hypothesis Generation and Testing Along the Value Chain 348
12.4 Conclusions 351
References 351
13 Applications of Physiologically Based Pharmacokinetic Models Integrated With Drug Effect Models (Pbpk/Pd) 353
13.1 Introduction: Integration of PBPK with Drug Effect Models 354
13.2 Dosing in Specific Populations 355
13.3...
Acknowledgements xxi
About the companion xxiii
Section I. Principles, Methods, andBackground Information 1
1 A Review of Pharmacokinetic and Pharmacodynamic Principles 3
1.1 Introduction 4
1.2 Pharmacokinetic Principles 4
1.2.1 Routes of Drug Administration 4
1.2.2 Intravenous Bolus 4
1.2.3 Plasma Protein Binding and Blood-Plasma Ratio 9
1.2.4 Hepatic, Renal, and Biliary Clearances 12
1.2.5 Extravascular (Subcutaneous, Intramuscular, and Per Oral) Absorption 16
1.2.6 Absorption from Solid Dosage Forms 20
1.2.7 Role of Transporters in ADME 22
1.2.8 Linear and Non-Linear Pharmacokinetics 24
1.2.9 Intravenous Infusion, Repeated Dosing, Steady State Kinetics, and Accumulation 25
1.2.10 Active Metabolite and Prodrug Kinetics 28
1.3 Pharmacokinetic Variability 32
1.4 Pharmacokinetics Optimization in Drug Discovery 34
1.5 Pharmacodynamic Principles 34
1.5.1 Pharmacological Targets and Drug Action 35
1.5.2 Functional Adaptation Processes 39
1.5.3 Biomarkers, Surrogate Endpoints, and Clinical Endpoints 41
Keywords 47
References 48
2 A Review of Drug-Drug Interactions 51
2.1 Introduction 51
2.2 Drug Interactions Mediated by Enzymes and Transporters at Various Sites 54
2.3 Factors Affecting DDI 54
2.4 In Vitro Methods to Evaluate Drug-Drug Interactions 56
2.4.1 Candidate Drug as a Potential Perpetrator 57
2.4.2 Candidate Drug as a Potential Victim of Inhibition 58
2.5 Sources of Uncertainty 59
2.6 Therapeutic Protein-Drug Interaction 59
References 61
3 Modeling Pharmacokinetics, Pharmacodynamics, And Drug Interactions 65
3.1 Introduction 66
3.2 Modeling Pharmacokinetics 66
3.2.1 Compartmental Modeling of Linear and Nonlinear Pharmacokinetics (Enzyme and/or Transporter Capacity Limitation as Well as Target-Mediated Drug Disposition) 67
3.2.2 Population Pharmacokinetics 76
3.3 Pharmacokinetics/Pharmacodynamics and PK/Efficacy (Exposure/ Response) Modeling 80
3.3.1 PK/PD Models for Direct Effect: Sigmoid Emax Model 84
3.3.2 PK/PD Models for Direct Effect: Classical Receptor Theory 86
3.3.3 PK/PD Models Accommodating Delayed Pharmacological Response 89
3.3.4 PK/PD Models Accommodating Functional Adaptation Leading to Nonlinearity in Pharmacological Response with Respect to Time 96
3.3.5 PK/Efficacy Modeling 97
3.3.6 Translation of PK/PD and PK/Efficacy Modeling to Human 100
3.3.7 Average, Minimum, and Maximum Steady-State Concentrations 104
3.3.8 Estimation of Biologically Effective Dose in Human 107
3.3.9 Therapeutic Window 109
3.3.10 Static Models for Drug Interactions 109
3.4 Physiologically Based Pharmacokinetic (PBPK) Modeling and Its Integration with Pharmacodynamics and Efficacy Models 112
3.4.1 PK Modeling Compartmental vs PBPK 112
3.4.2 PK Variability: Population PK (popPK) Modeling vs PBPK 114
3.4.3 Integration of PBPK with PD, Quantitative Systems Pharmacology (QSP) Models or Quantitative Systems Toxicologyand Safety (QSTS) 114
3.4.4 PBPK Models to Evaluate Drug-Drug Interactions 115
3.4.5 DDI Risk Assessment with PBPK vs Static Models 118
Keywords 123
References 125
4 Physiological Model For Absorption 129
4.1 Introduction 130
4.2 Drug Absorption and Gut Bioavailability 130
4.2.1 Solubility and Dissolution Rate 130
4.2.2 Permeability: Transcellular, Paracellular, and Carrier-Mediated Pathways 136
4.2.3 Barriers to Membrane Transport - Luminal Degradation, Efflux, and Gut Metabolism 138
4.3 Factors Affecting Drug Absorption and Gut Bioavailability 140
4.3.1 Physiological Factors Affecting Oral Drug Absorption and Species Differences in Physiology 140
4.3.2 Compound-Dependent Factors 144
4.3.3 Formulation-Dependent Factors 144
4.4 In Silico Predictions of Passive Permeability and Solubility 147
4.4.1 In Silico Models for Permeability 147
4.4.2 In Silico Models for Solubility 147
4.5 Measurement of Permeability, Solubility, Luminal Stability, Efflux, Intestinal Metabolism 148
4.5.1 In Vitro, In Situ, and In Vivo Models for Effective Permeability 148
4.5.2 Measurement of Thermodynamic or Equilibrium Solubility 153
4.5.3 Luminal Stability 154
4.5.4 Efflux 154
4.5.5 In Vitro Models for Gut Metabolism and Estimation of Fraction Escaping Gut Metabolism 155
4.6 Absorption Modeling 156
Keywords 162
References 163
5 Physiological Model For Distribution 169
5.1 Introduction 170
5.2 Factors Affecting Tissue Distribution of Xenobiotics 170
5.2.1 Physiological Factors and Species Differences in Physiology 171
5.2.2 Compound-Dependent Factors 176
5.3 In Silico Models of Tissue Partition Coefficients 176
5.4 Measurement of Parameters Representing the Rate and Extent of Tissue Distribution 181
5.4.1 Assessment of Rate and Extent of Brain Penetration 181
5.5 Physiological Model for Drug Distribution 186
5.6 Drug Concentrations at the Site of Action 187
Keywords 189
References 189
6 Physiological Models For Drug Metabolism And Excretion 193
6.1 Introduction 193
6.2 Factors Affecting Drug Metabolism and Excretion of Xenobiotics 194
6.3 Models for Hepatobiliary and Renal Excretion 197
6.3.1 In Silico Models 197
6.3.2 In Vitro Models for Hepatic Metabolism 197
6.3.3 In Vitro Models for Transporters 200
6.4 Physiological Models 203
6.4.1 Hepato-Biliary Elimination of Parent Drug and Metabolites 205
6.4.2 Renal Excretion 208
References 211
7 Generic Whole-Body Physiologically Based Pharmacokinetic Modeling 217
7.1 Introduction 217
7.2 Structure of a Generic Physiologically-Based Pharmacokinetic (PBPK) Model 218
7.3 Somatic Compartments 220
7.3.1 Lungs (LU) 220
7.3.2 Arterial Blood (ART) 220
7.3.3 Venous Blood (VEN) 220
7.3.4 Stomach (ST) 220
7.3.5 Gut (GU) 220
7.4 Model Assumptions 221
7.5 PBPK Software 221
References 223
8 Pbpk Modeling Of Biotherapeutics 225
8.1 Introduction 226
8.2 Therapeutic Proteins 226
8.2.1 Peptides and Proteins 226
8.2.2 Antibodies and Antibody-Based Therapies 227
8.3 Pharmacokinetics of Therapeutic Proteins 234
8.3.1 Absorption 234
8.3.2 Renal Elimination 235
8.3.3 Immunogenicity 235
8.3.4 PEGylation 239
8.3.5 Transport by Convective and Transcytotic Extravasation 239
8.3.6 Catabolic Elimination (Proteolysis) 239
8.3.7 FcRn-Mediated Protection of IgGs Against Catabolism in FcRn-Rich Cells 241
8.3.8 Distribution and lymphatic elimination 242
8.3.9 Target-Mediated Drug Disposition and Receptor-Mediated Endocytosis 243
8.4 PBPK Modeling of Monoclonal Antibodies 244
8.4.1 Full PBPK Model for Monoclonal Antibodies 244
8.4.2 Minimal PBPK Model for Monoclonal Antibodies 253
8.5 Applications of PBPK Modeling of Monoclonal Antibodies 253
8.5.1 Pharmacokinetic Scaling 253
8.5.2 PBPK Integration with Pharmacodynamics of Monoclonal Antibodies 255
Keywords 156
References 258
9 Uncertainty And Population Variability 263
9.1 Introduction 264
9.2 Distinguishing Uncertainty and Variability 264
9.3 Sources of Uncertainty in Drug-related Parameters 264
9.4 Sources of Variability in System Parameters 266
9.5 Handling Population Variability 269
9.5.1 A POSTERIORI and A PRIORI Approaches to Handling Population Variability 269
9.5.2 Correlations Between Parameters 271
9.6 Uncertainty and Sensitivity Analysis 272
9.6.1 Local Sensitivity Analysis (One-at-a-time (OAT) and Derivative-based Methods) 272
9.6.2 Parameter Interactions and Global Sensitivity Analysis (GSA) 275
9.6.3 Global Sensitivity Analysis for Correlated Parameters (cGSA) 278
9.6.4 Applications of Sensitivity Analysis for PBPK Models 280
9.6.5 Limitations of Global Sensitivity Analysis 281
9.7 Uncertainty and Population Variability in Clinical Efficacy and Safety 282
Keywords 285
References 285
10 Nonclinical, Clinical, and Model-Informed Drug Development 293
10.1 Introduction: An Overview of Different Phases of Drug Development 294
10.2 Nonclinical Development 295
10.2.1 Preclinical Pharmacology, PK/PD Modeling, and Human Dose Prediction 297
10.2.2 Safety and Toxicology Studies 297
10.2.3 Studies with Radiolabeled Compound 298
10.3 Clinical Pharmacology Studies 302
10.3.1 First-in-Human, Single, and Multiple Ascending Dose Studies 302
10.3.2 Biopharmaceutics - Absolute Oral Bioavailability and Bioequivalence Study 304
10.3.3 Food Effect Study 304
10.3.4 Organ (Hepatic and Renal) Impairment Study 305
10.3.5 Pediatric Assessment 306
10.3.6 Mass Balance Study 307
10.3.7 Drug Interaction Study 307
10.3.8 Pharmacogenomics Study 308
10.3.9 Thorough QT (TQT) and Concentration QT (C-QT) Study 308
10.3.10 Immunogenicity Assays and Comparability Study for Biologics 309
10.3.11 Drug Labelling 309
10.4 Clinical Development in Oncology 310
10.5 Fast Track Routes to Address Unmet Medical Need in the Treatment of Serious Conditions 311
10.6 Model-Informed Drug Development 312
10.7 Physiologically Based Pharmacokinetic Models Complementing Clinical Pharmacology Studies 314
10.8 PBPK in Oncology 315
Regulatory Guidelines 316
References 319
Section II. Applications In The Pharmaceutical Industry 323
11 Overview Of Pbpk Applications 325
11.1 Introduction 325
11.2 PBPK Applications for Internal Decisions 326
11.3 PBPK Applications for Regulatory Filing 328
11.4 PBPK Modeling and Simulations Along the Value Chain 332
References 335
12 Applications Of Hypothesis Generation And Testing With Pbpk Models 337
12.1 Introduction 338
12.2 Hypothesis Generation and Testing with PBPK Models 338
12.2.1 Parameter Estimation from Intravenous Pharmacokinetic Profiles 338
12.2.2 Simulation of Oral PK Profile 341
12.2.3 Sensitivity Analysis 342
12.2.4 Verification of Hypotheses 346
12.2.5 Auto-inhibition of Drug-Metabolizing Enzymes, Uptake and Efflux Transporters 347
12.3 Hypothesis Generation and Testing Along the Value Chain 348
12.4 Conclusions 351
References 351
13 Applications of Physiologically Based Pharmacokinetic Models Integrated With Drug Effect Models (Pbpk/Pd) 353
13.1 Introduction: Integration of PBPK with Drug Effect Models 354
13.2 Dosing in Specific Populations 355
13.3...
Details
| Erscheinungsjahr: | 2021 |
|---|---|
| Fachbereich: | Populäre Darstellungen |
| Genre: | Chemie |
| Rubrik: | Naturwissenschaften & Technik |
| Medium: | Buch |
| Seiten: | 624 |
| Inhalt: | 624 S. |
| ISBN-13: | 9781119497684 |
| ISBN-10: | 111949768X |
| Sprache: | Englisch |
| Herstellernummer: | 1W119497680 |
| Einband: | Gebunden |
| Autor: | Peters, Sheila Annie |
| Auflage: | 2nd edition |
| Hersteller: | Turner Publishing Company |
| Maße: | 235 x 157 x 38 mm |
| Von/Mit: | Sheila Annie Peters |
| Erscheinungsdatum: | 12.10.2021 |
| Gewicht: | 1,06 kg |
Über den Autor
Sheila Annie Peters, PhD, is Head of Translational Quantitative Pharmacology at Merck Healthcare, Darmstadt, Germany. Previously, she was an Associate Principal Scientist for Discovery DMPK and Bioanalytical Chemistry at AstraZeneca and Principal Scientist at Cyprotex Discovery. She has lectured at the Regional Engineering College (Trichy, India) and University of Madras and Pondicherry University.
Inhaltsverzeichnis
Preface xix
Acknowledgements xxi
About the companion xxiii
Section I. Principles, Methods, andBackground Information 1
1 A Review of Pharmacokinetic and Pharmacodynamic Principles 3
1.1 Introduction 4
1.2 Pharmacokinetic Principles 4
1.2.1 Routes of Drug Administration 4
1.2.2 Intravenous Bolus 4
1.2.3 Plasma Protein Binding and Blood-Plasma Ratio 9
1.2.4 Hepatic, Renal, and Biliary Clearances 12
1.2.5 Extravascular (Subcutaneous, Intramuscular, and Per Oral) Absorption 16
1.2.6 Absorption from Solid Dosage Forms 20
1.2.7 Role of Transporters in ADME 22
1.2.8 Linear and Non-Linear Pharmacokinetics 24
1.2.9 Intravenous Infusion, Repeated Dosing, Steady State Kinetics, and Accumulation 25
1.2.10 Active Metabolite and Prodrug Kinetics 28
1.3 Pharmacokinetic Variability 32
1.4 Pharmacokinetics Optimization in Drug Discovery 34
1.5 Pharmacodynamic Principles 34
1.5.1 Pharmacological Targets and Drug Action 35
1.5.2 Functional Adaptation Processes 39
1.5.3 Biomarkers, Surrogate Endpoints, and Clinical Endpoints 41
Keywords 47
References 48
2 A Review of Drug-Drug Interactions 51
2.1 Introduction 51
2.2 Drug Interactions Mediated by Enzymes and Transporters at Various Sites 54
2.3 Factors Affecting DDI 54
2.4 In Vitro Methods to Evaluate Drug-Drug Interactions 56
2.4.1 Candidate Drug as a Potential Perpetrator 57
2.4.2 Candidate Drug as a Potential Victim of Inhibition 58
2.5 Sources of Uncertainty 59
2.6 Therapeutic Protein-Drug Interaction 59
References 61
3 Modeling Pharmacokinetics, Pharmacodynamics, And Drug Interactions 65
3.1 Introduction 66
3.2 Modeling Pharmacokinetics 66
3.2.1 Compartmental Modeling of Linear and Nonlinear Pharmacokinetics (Enzyme and/or Transporter Capacity Limitation as Well as Target-Mediated Drug Disposition) 67
3.2.2 Population Pharmacokinetics 76
3.3 Pharmacokinetics/Pharmacodynamics and PK/Efficacy (Exposure/ Response) Modeling 80
3.3.1 PK/PD Models for Direct Effect: Sigmoid Emax Model 84
3.3.2 PK/PD Models for Direct Effect: Classical Receptor Theory 86
3.3.3 PK/PD Models Accommodating Delayed Pharmacological Response 89
3.3.4 PK/PD Models Accommodating Functional Adaptation Leading to Nonlinearity in Pharmacological Response with Respect to Time 96
3.3.5 PK/Efficacy Modeling 97
3.3.6 Translation of PK/PD and PK/Efficacy Modeling to Human 100
3.3.7 Average, Minimum, and Maximum Steady-State Concentrations 104
3.3.8 Estimation of Biologically Effective Dose in Human 107
3.3.9 Therapeutic Window 109
3.3.10 Static Models for Drug Interactions 109
3.4 Physiologically Based Pharmacokinetic (PBPK) Modeling and Its Integration with Pharmacodynamics and Efficacy Models 112
3.4.1 PK Modeling Compartmental vs PBPK 112
3.4.2 PK Variability: Population PK (popPK) Modeling vs PBPK 114
3.4.3 Integration of PBPK with PD, Quantitative Systems Pharmacology (QSP) Models or Quantitative Systems Toxicologyand Safety (QSTS) 114
3.4.4 PBPK Models to Evaluate Drug-Drug Interactions 115
3.4.5 DDI Risk Assessment with PBPK vs Static Models 118
Keywords 123
References 125
4 Physiological Model For Absorption 129
4.1 Introduction 130
4.2 Drug Absorption and Gut Bioavailability 130
4.2.1 Solubility and Dissolution Rate 130
4.2.2 Permeability: Transcellular, Paracellular, and Carrier-Mediated Pathways 136
4.2.3 Barriers to Membrane Transport - Luminal Degradation, Efflux, and Gut Metabolism 138
4.3 Factors Affecting Drug Absorption and Gut Bioavailability 140
4.3.1 Physiological Factors Affecting Oral Drug Absorption and Species Differences in Physiology 140
4.3.2 Compound-Dependent Factors 144
4.3.3 Formulation-Dependent Factors 144
4.4 In Silico Predictions of Passive Permeability and Solubility 147
4.4.1 In Silico Models for Permeability 147
4.4.2 In Silico Models for Solubility 147
4.5 Measurement of Permeability, Solubility, Luminal Stability, Efflux, Intestinal Metabolism 148
4.5.1 In Vitro, In Situ, and In Vivo Models for Effective Permeability 148
4.5.2 Measurement of Thermodynamic or Equilibrium Solubility 153
4.5.3 Luminal Stability 154
4.5.4 Efflux 154
4.5.5 In Vitro Models for Gut Metabolism and Estimation of Fraction Escaping Gut Metabolism 155
4.6 Absorption Modeling 156
Keywords 162
References 163
5 Physiological Model For Distribution 169
5.1 Introduction 170
5.2 Factors Affecting Tissue Distribution of Xenobiotics 170
5.2.1 Physiological Factors and Species Differences in Physiology 171
5.2.2 Compound-Dependent Factors 176
5.3 In Silico Models of Tissue Partition Coefficients 176
5.4 Measurement of Parameters Representing the Rate and Extent of Tissue Distribution 181
5.4.1 Assessment of Rate and Extent of Brain Penetration 181
5.5 Physiological Model for Drug Distribution 186
5.6 Drug Concentrations at the Site of Action 187
Keywords 189
References 189
6 Physiological Models For Drug Metabolism And Excretion 193
6.1 Introduction 193
6.2 Factors Affecting Drug Metabolism and Excretion of Xenobiotics 194
6.3 Models for Hepatobiliary and Renal Excretion 197
6.3.1 In Silico Models 197
6.3.2 In Vitro Models for Hepatic Metabolism 197
6.3.3 In Vitro Models for Transporters 200
6.4 Physiological Models 203
6.4.1 Hepato-Biliary Elimination of Parent Drug and Metabolites 205
6.4.2 Renal Excretion 208
References 211
7 Generic Whole-Body Physiologically Based Pharmacokinetic Modeling 217
7.1 Introduction 217
7.2 Structure of a Generic Physiologically-Based Pharmacokinetic (PBPK) Model 218
7.3 Somatic Compartments 220
7.3.1 Lungs (LU) 220
7.3.2 Arterial Blood (ART) 220
7.3.3 Venous Blood (VEN) 220
7.3.4 Stomach (ST) 220
7.3.5 Gut (GU) 220
7.4 Model Assumptions 221
7.5 PBPK Software 221
References 223
8 Pbpk Modeling Of Biotherapeutics 225
8.1 Introduction 226
8.2 Therapeutic Proteins 226
8.2.1 Peptides and Proteins 226
8.2.2 Antibodies and Antibody-Based Therapies 227
8.3 Pharmacokinetics of Therapeutic Proteins 234
8.3.1 Absorption 234
8.3.2 Renal Elimination 235
8.3.3 Immunogenicity 235
8.3.4 PEGylation 239
8.3.5 Transport by Convective and Transcytotic Extravasation 239
8.3.6 Catabolic Elimination (Proteolysis) 239
8.3.7 FcRn-Mediated Protection of IgGs Against Catabolism in FcRn-Rich Cells 241
8.3.8 Distribution and lymphatic elimination 242
8.3.9 Target-Mediated Drug Disposition and Receptor-Mediated Endocytosis 243
8.4 PBPK Modeling of Monoclonal Antibodies 244
8.4.1 Full PBPK Model for Monoclonal Antibodies 244
8.4.2 Minimal PBPK Model for Monoclonal Antibodies 253
8.5 Applications of PBPK Modeling of Monoclonal Antibodies 253
8.5.1 Pharmacokinetic Scaling 253
8.5.2 PBPK Integration with Pharmacodynamics of Monoclonal Antibodies 255
Keywords 156
References 258
9 Uncertainty And Population Variability 263
9.1 Introduction 264
9.2 Distinguishing Uncertainty and Variability 264
9.3 Sources of Uncertainty in Drug-related Parameters 264
9.4 Sources of Variability in System Parameters 266
9.5 Handling Population Variability 269
9.5.1 A POSTERIORI and A PRIORI Approaches to Handling Population Variability 269
9.5.2 Correlations Between Parameters 271
9.6 Uncertainty and Sensitivity Analysis 272
9.6.1 Local Sensitivity Analysis (One-at-a-time (OAT) and Derivative-based Methods) 272
9.6.2 Parameter Interactions and Global Sensitivity Analysis (GSA) 275
9.6.3 Global Sensitivity Analysis for Correlated Parameters (cGSA) 278
9.6.4 Applications of Sensitivity Analysis for PBPK Models 280
9.6.5 Limitations of Global Sensitivity Analysis 281
9.7 Uncertainty and Population Variability in Clinical Efficacy and Safety 282
Keywords 285
References 285
10 Nonclinical, Clinical, and Model-Informed Drug Development 293
10.1 Introduction: An Overview of Different Phases of Drug Development 294
10.2 Nonclinical Development 295
10.2.1 Preclinical Pharmacology, PK/PD Modeling, and Human Dose Prediction 297
10.2.2 Safety and Toxicology Studies 297
10.2.3 Studies with Radiolabeled Compound 298
10.3 Clinical Pharmacology Studies 302
10.3.1 First-in-Human, Single, and Multiple Ascending Dose Studies 302
10.3.2 Biopharmaceutics - Absolute Oral Bioavailability and Bioequivalence Study 304
10.3.3 Food Effect Study 304
10.3.4 Organ (Hepatic and Renal) Impairment Study 305
10.3.5 Pediatric Assessment 306
10.3.6 Mass Balance Study 307
10.3.7 Drug Interaction Study 307
10.3.8 Pharmacogenomics Study 308
10.3.9 Thorough QT (TQT) and Concentration QT (C-QT) Study 308
10.3.10 Immunogenicity Assays and Comparability Study for Biologics 309
10.3.11 Drug Labelling 309
10.4 Clinical Development in Oncology 310
10.5 Fast Track Routes to Address Unmet Medical Need in the Treatment of Serious Conditions 311
10.6 Model-Informed Drug Development 312
10.7 Physiologically Based Pharmacokinetic Models Complementing Clinical Pharmacology Studies 314
10.8 PBPK in Oncology 315
Regulatory Guidelines 316
References 319
Section II. Applications In The Pharmaceutical Industry 323
11 Overview Of Pbpk Applications 325
11.1 Introduction 325
11.2 PBPK Applications for Internal Decisions 326
11.3 PBPK Applications for Regulatory Filing 328
11.4 PBPK Modeling and Simulations Along the Value Chain 332
References 335
12 Applications Of Hypothesis Generation And Testing With Pbpk Models 337
12.1 Introduction 338
12.2 Hypothesis Generation and Testing with PBPK Models 338
12.2.1 Parameter Estimation from Intravenous Pharmacokinetic Profiles 338
12.2.2 Simulation of Oral PK Profile 341
12.2.3 Sensitivity Analysis 342
12.2.4 Verification of Hypotheses 346
12.2.5 Auto-inhibition of Drug-Metabolizing Enzymes, Uptake and Efflux Transporters 347
12.3 Hypothesis Generation and Testing Along the Value Chain 348
12.4 Conclusions 351
References 351
13 Applications of Physiologically Based Pharmacokinetic Models Integrated With Drug Effect Models (Pbpk/Pd) 353
13.1 Introduction: Integration of PBPK with Drug Effect Models 354
13.2 Dosing in Specific Populations 355
13.3...
Acknowledgements xxi
About the companion xxiii
Section I. Principles, Methods, andBackground Information 1
1 A Review of Pharmacokinetic and Pharmacodynamic Principles 3
1.1 Introduction 4
1.2 Pharmacokinetic Principles 4
1.2.1 Routes of Drug Administration 4
1.2.2 Intravenous Bolus 4
1.2.3 Plasma Protein Binding and Blood-Plasma Ratio 9
1.2.4 Hepatic, Renal, and Biliary Clearances 12
1.2.5 Extravascular (Subcutaneous, Intramuscular, and Per Oral) Absorption 16
1.2.6 Absorption from Solid Dosage Forms 20
1.2.7 Role of Transporters in ADME 22
1.2.8 Linear and Non-Linear Pharmacokinetics 24
1.2.9 Intravenous Infusion, Repeated Dosing, Steady State Kinetics, and Accumulation 25
1.2.10 Active Metabolite and Prodrug Kinetics 28
1.3 Pharmacokinetic Variability 32
1.4 Pharmacokinetics Optimization in Drug Discovery 34
1.5 Pharmacodynamic Principles 34
1.5.1 Pharmacological Targets and Drug Action 35
1.5.2 Functional Adaptation Processes 39
1.5.3 Biomarkers, Surrogate Endpoints, and Clinical Endpoints 41
Keywords 47
References 48
2 A Review of Drug-Drug Interactions 51
2.1 Introduction 51
2.2 Drug Interactions Mediated by Enzymes and Transporters at Various Sites 54
2.3 Factors Affecting DDI 54
2.4 In Vitro Methods to Evaluate Drug-Drug Interactions 56
2.4.1 Candidate Drug as a Potential Perpetrator 57
2.4.2 Candidate Drug as a Potential Victim of Inhibition 58
2.5 Sources of Uncertainty 59
2.6 Therapeutic Protein-Drug Interaction 59
References 61
3 Modeling Pharmacokinetics, Pharmacodynamics, And Drug Interactions 65
3.1 Introduction 66
3.2 Modeling Pharmacokinetics 66
3.2.1 Compartmental Modeling of Linear and Nonlinear Pharmacokinetics (Enzyme and/or Transporter Capacity Limitation as Well as Target-Mediated Drug Disposition) 67
3.2.2 Population Pharmacokinetics 76
3.3 Pharmacokinetics/Pharmacodynamics and PK/Efficacy (Exposure/ Response) Modeling 80
3.3.1 PK/PD Models for Direct Effect: Sigmoid Emax Model 84
3.3.2 PK/PD Models for Direct Effect: Classical Receptor Theory 86
3.3.3 PK/PD Models Accommodating Delayed Pharmacological Response 89
3.3.4 PK/PD Models Accommodating Functional Adaptation Leading to Nonlinearity in Pharmacological Response with Respect to Time 96
3.3.5 PK/Efficacy Modeling 97
3.3.6 Translation of PK/PD and PK/Efficacy Modeling to Human 100
3.3.7 Average, Minimum, and Maximum Steady-State Concentrations 104
3.3.8 Estimation of Biologically Effective Dose in Human 107
3.3.9 Therapeutic Window 109
3.3.10 Static Models for Drug Interactions 109
3.4 Physiologically Based Pharmacokinetic (PBPK) Modeling and Its Integration with Pharmacodynamics and Efficacy Models 112
3.4.1 PK Modeling Compartmental vs PBPK 112
3.4.2 PK Variability: Population PK (popPK) Modeling vs PBPK 114
3.4.3 Integration of PBPK with PD, Quantitative Systems Pharmacology (QSP) Models or Quantitative Systems Toxicologyand Safety (QSTS) 114
3.4.4 PBPK Models to Evaluate Drug-Drug Interactions 115
3.4.5 DDI Risk Assessment with PBPK vs Static Models 118
Keywords 123
References 125
4 Physiological Model For Absorption 129
4.1 Introduction 130
4.2 Drug Absorption and Gut Bioavailability 130
4.2.1 Solubility and Dissolution Rate 130
4.2.2 Permeability: Transcellular, Paracellular, and Carrier-Mediated Pathways 136
4.2.3 Barriers to Membrane Transport - Luminal Degradation, Efflux, and Gut Metabolism 138
4.3 Factors Affecting Drug Absorption and Gut Bioavailability 140
4.3.1 Physiological Factors Affecting Oral Drug Absorption and Species Differences in Physiology 140
4.3.2 Compound-Dependent Factors 144
4.3.3 Formulation-Dependent Factors 144
4.4 In Silico Predictions of Passive Permeability and Solubility 147
4.4.1 In Silico Models for Permeability 147
4.4.2 In Silico Models for Solubility 147
4.5 Measurement of Permeability, Solubility, Luminal Stability, Efflux, Intestinal Metabolism 148
4.5.1 In Vitro, In Situ, and In Vivo Models for Effective Permeability 148
4.5.2 Measurement of Thermodynamic or Equilibrium Solubility 153
4.5.3 Luminal Stability 154
4.5.4 Efflux 154
4.5.5 In Vitro Models for Gut Metabolism and Estimation of Fraction Escaping Gut Metabolism 155
4.6 Absorption Modeling 156
Keywords 162
References 163
5 Physiological Model For Distribution 169
5.1 Introduction 170
5.2 Factors Affecting Tissue Distribution of Xenobiotics 170
5.2.1 Physiological Factors and Species Differences in Physiology 171
5.2.2 Compound-Dependent Factors 176
5.3 In Silico Models of Tissue Partition Coefficients 176
5.4 Measurement of Parameters Representing the Rate and Extent of Tissue Distribution 181
5.4.1 Assessment of Rate and Extent of Brain Penetration 181
5.5 Physiological Model for Drug Distribution 186
5.6 Drug Concentrations at the Site of Action 187
Keywords 189
References 189
6 Physiological Models For Drug Metabolism And Excretion 193
6.1 Introduction 193
6.2 Factors Affecting Drug Metabolism and Excretion of Xenobiotics 194
6.3 Models for Hepatobiliary and Renal Excretion 197
6.3.1 In Silico Models 197
6.3.2 In Vitro Models for Hepatic Metabolism 197
6.3.3 In Vitro Models for Transporters 200
6.4 Physiological Models 203
6.4.1 Hepato-Biliary Elimination of Parent Drug and Metabolites 205
6.4.2 Renal Excretion 208
References 211
7 Generic Whole-Body Physiologically Based Pharmacokinetic Modeling 217
7.1 Introduction 217
7.2 Structure of a Generic Physiologically-Based Pharmacokinetic (PBPK) Model 218
7.3 Somatic Compartments 220
7.3.1 Lungs (LU) 220
7.3.2 Arterial Blood (ART) 220
7.3.3 Venous Blood (VEN) 220
7.3.4 Stomach (ST) 220
7.3.5 Gut (GU) 220
7.4 Model Assumptions 221
7.5 PBPK Software 221
References 223
8 Pbpk Modeling Of Biotherapeutics 225
8.1 Introduction 226
8.2 Therapeutic Proteins 226
8.2.1 Peptides and Proteins 226
8.2.2 Antibodies and Antibody-Based Therapies 227
8.3 Pharmacokinetics of Therapeutic Proteins 234
8.3.1 Absorption 234
8.3.2 Renal Elimination 235
8.3.3 Immunogenicity 235
8.3.4 PEGylation 239
8.3.5 Transport by Convective and Transcytotic Extravasation 239
8.3.6 Catabolic Elimination (Proteolysis) 239
8.3.7 FcRn-Mediated Protection of IgGs Against Catabolism in FcRn-Rich Cells 241
8.3.8 Distribution and lymphatic elimination 242
8.3.9 Target-Mediated Drug Disposition and Receptor-Mediated Endocytosis 243
8.4 PBPK Modeling of Monoclonal Antibodies 244
8.4.1 Full PBPK Model for Monoclonal Antibodies 244
8.4.2 Minimal PBPK Model for Monoclonal Antibodies 253
8.5 Applications of PBPK Modeling of Monoclonal Antibodies 253
8.5.1 Pharmacokinetic Scaling 253
8.5.2 PBPK Integration with Pharmacodynamics of Monoclonal Antibodies 255
Keywords 156
References 258
9 Uncertainty And Population Variability 263
9.1 Introduction 264
9.2 Distinguishing Uncertainty and Variability 264
9.3 Sources of Uncertainty in Drug-related Parameters 264
9.4 Sources of Variability in System Parameters 266
9.5 Handling Population Variability 269
9.5.1 A POSTERIORI and A PRIORI Approaches to Handling Population Variability 269
9.5.2 Correlations Between Parameters 271
9.6 Uncertainty and Sensitivity Analysis 272
9.6.1 Local Sensitivity Analysis (One-at-a-time (OAT) and Derivative-based Methods) 272
9.6.2 Parameter Interactions and Global Sensitivity Analysis (GSA) 275
9.6.3 Global Sensitivity Analysis for Correlated Parameters (cGSA) 278
9.6.4 Applications of Sensitivity Analysis for PBPK Models 280
9.6.5 Limitations of Global Sensitivity Analysis 281
9.7 Uncertainty and Population Variability in Clinical Efficacy and Safety 282
Keywords 285
References 285
10 Nonclinical, Clinical, and Model-Informed Drug Development 293
10.1 Introduction: An Overview of Different Phases of Drug Development 294
10.2 Nonclinical Development 295
10.2.1 Preclinical Pharmacology, PK/PD Modeling, and Human Dose Prediction 297
10.2.2 Safety and Toxicology Studies 297
10.2.3 Studies with Radiolabeled Compound 298
10.3 Clinical Pharmacology Studies 302
10.3.1 First-in-Human, Single, and Multiple Ascending Dose Studies 302
10.3.2 Biopharmaceutics - Absolute Oral Bioavailability and Bioequivalence Study 304
10.3.3 Food Effect Study 304
10.3.4 Organ (Hepatic and Renal) Impairment Study 305
10.3.5 Pediatric Assessment 306
10.3.6 Mass Balance Study 307
10.3.7 Drug Interaction Study 307
10.3.8 Pharmacogenomics Study 308
10.3.9 Thorough QT (TQT) and Concentration QT (C-QT) Study 308
10.3.10 Immunogenicity Assays and Comparability Study for Biologics 309
10.3.11 Drug Labelling 309
10.4 Clinical Development in Oncology 310
10.5 Fast Track Routes to Address Unmet Medical Need in the Treatment of Serious Conditions 311
10.6 Model-Informed Drug Development 312
10.7 Physiologically Based Pharmacokinetic Models Complementing Clinical Pharmacology Studies 314
10.8 PBPK in Oncology 315
Regulatory Guidelines 316
References 319
Section II. Applications In The Pharmaceutical Industry 323
11 Overview Of Pbpk Applications 325
11.1 Introduction 325
11.2 PBPK Applications for Internal Decisions 326
11.3 PBPK Applications for Regulatory Filing 328
11.4 PBPK Modeling and Simulations Along the Value Chain 332
References 335
12 Applications Of Hypothesis Generation And Testing With Pbpk Models 337
12.1 Introduction 338
12.2 Hypothesis Generation and Testing with PBPK Models 338
12.2.1 Parameter Estimation from Intravenous Pharmacokinetic Profiles 338
12.2.2 Simulation of Oral PK Profile 341
12.2.3 Sensitivity Analysis 342
12.2.4 Verification of Hypotheses 346
12.2.5 Auto-inhibition of Drug-Metabolizing Enzymes, Uptake and Efflux Transporters 347
12.3 Hypothesis Generation and Testing Along the Value Chain 348
12.4 Conclusions 351
References 351
13 Applications of Physiologically Based Pharmacokinetic Models Integrated With Drug Effect Models (Pbpk/Pd) 353
13.1 Introduction: Integration of PBPK with Drug Effect Models 354
13.2 Dosing in Specific Populations 355
13.3...
Details
| Erscheinungsjahr: | 2021 |
|---|---|
| Fachbereich: | Populäre Darstellungen |
| Genre: | Chemie |
| Rubrik: | Naturwissenschaften & Technik |
| Medium: | Buch |
| Seiten: | 624 |
| Inhalt: | 624 S. |
| ISBN-13: | 9781119497684 |
| ISBN-10: | 111949768X |
| Sprache: | Englisch |
| Herstellernummer: | 1W119497680 |
| Einband: | Gebunden |
| Autor: | Peters, Sheila Annie |
| Auflage: | 2nd edition |
| Hersteller: | Turner Publishing Company |
| Maße: | 235 x 157 x 38 mm |
| Von/Mit: | Sheila Annie Peters |
| Erscheinungsdatum: | 12.10.2021 |
| Gewicht: | 1,06 kg |
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