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Fachgebiet | Biowissenschaften | Zell- u. Molekularbiologie | Lieferbare Titel | Pharmacokinetics and Pharmacodynamics of Biotech Drugs | Inhaltsverzeichnis
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  Contents  
 
  Foreword V
  Preface VII
  List of Contributors XIX
  Part I: Introduction  
1 The Role of Pharmacokinetics and Pharmacodynamics in the Development of Biotech Drugs
Bernd Meibohm 		3
1.1 Introduction 3
1.2 Biotech Drugs and the Pharmaceutical Industry 4
1.3 Pharmacokinetics and Pharmacodynamics in Drug Development 6
1.4 PK and PK/PD Pitfalls for Biotech Drugs 9
1.5 Regulatory Guidance 10
1.6 Future 10
1.7 References 12
  Part II: The Basics  
2 Pharmacokinetics of Peptides and Proteins
Lisa Tang and Bernd Meibohm 		17
2.1 Introduction 17
2.2 Administration Pathways 18
2.2.1 Administration by Injection or Infusion 18
2.2.2 Inhalational Administration 23
2.2.3 Intranasal Administration 24
2.2.4 Transdermal Administration 25
2.2.5 Peroral Administration 25
2.3 Administration Route and Immunogenicity 27
2.4 Distribution 28
2.5 Elimination 29
2.5.1 Proteolysis 32
2.5.2 Gastrointestinal Elimination 32
2.5.3 Renal Elimination 32
2.5.4 Hepatic Elimination 34
2.5.5 Receptor-Mediated Endocytosis 35
2.6 Interspecies Scaling 36
2.7 Conclusions 37
2.8 References 38
3 Pharmacokinetics of Monoclonal Antibodies
Katharina Kuester and Charlotte Kloft 		45
3.1 Introduction 45
3.2 The Human Immune System 46
3.2.1 The Cellular Immune Response 47
3.2.2 The Humoral Immune Response 47
3.3 Physiological Antibodies 48
3.3.1 Classes of Antibodies 48
3.3.1.1 Immunoglobulin G 48
3.3.1.2 Immunoglobulins A, D, M, and E 49
3.3.2 Chemical Structure of Antibodies 50
3.4 Therapeutic Antibodies 52
3.4.1 Therapeutic Polyclonal Antibodies 52
3.4.2 Therapeutic mAbs 53
3.4.2.1 Murine mAbs 53
3.4.2.2 Chimeric mAbs 55
3.4.2.3 Humanized mAbs 55
3.4.2.4 Human mAbs 55
3.4.2.5 Further Species of mAbs 56
3.5 Effector Functions and Modes of Action of Antibodies 58
3.5.1 Biological Effector Functions of mAbs 58
3.5.2 Modes of Action of mAbs 59
3.5.2.1 Antibody-Dependent Cellular Cytotoxicity (ADCC) 59
3.5.2.2 Complement-Dependent Cytotoxicity 60
3.5.2.3 Blockage of Interaction between (Patho)Physiological Substance and Antigen 61
3.5.2.4 Conjugated Unlabeled mAbs 61
3.5.2.5 Radioactively Labeled mAbs 61
3.6 Prerequisites for mAb Therapy 62
3.6.1 The Patient 62
3.6.2 The Antibody 63
3.6.3 The Target Cell 63
3.6.4 The Antigen 63
3.7 Issues in the Bioanalysis of Antibodies 64
3.8 Catabolism of Antibodies 65
3.8.1 Proteolytic Degradation 65
3.8.2 Neonatal Fc Receptor (Fc-Rn) 65
3.9 Pharmacokinetic Characteristics of mAbs 68
3.9.1 Absorption 68
3.9.2 Distribution 71
3.9.2.1 Transport 71
3.9.2.2 Volume of Distribution 72
3.9.2.3 Types of Binding 74
3.9.3 Elimination 76
3.9.3.1 Clearance 76
3.9.3.2 Proteolysis 76
3.9.3.3 Binding to Antigen 77
3.9.3.4 Binding to Anti-Idiotype Antibodies 77
3.9.3.5 Drug Interaction Studies 78
3.9.4 Comparison of Pharmacokinetics of mAbs and Traditional Small-Molecule Drugs 78
3.10 Pharmacokinetic Modeling of mAbs 79
3.10.1 Noncompartmental Pharmacokinetic Analysis 79
3.10.2 Individual Compartmental Pharmacokinetic Analysis 80
3.10.3 Population Pharmacokinetic Analysis 81
3.10.3.1 Structural Submodel 82
3.10.3.2 Statistical Submodel 85
3.10.3.3 Covariate Submodel 85
3.11 Pharmacodynamics of mAbs 86
3.12 Conclusions 90
3.13 References 91
4 Pharmacokinetics and Pharmacodynamics of Antisense Oligonucleotides
Rosie Z. Yu, Richard S. Geary, and Arthur A. Levin 		93
4.1 Introduction 93
4.2 Pharmacokinetics 96
4.2.1 Plasma Pharmacokinetics Across Species 97
4.2.2 Tissue Distribution 100
4.2.3 Metabolism 102
4.2.4 Elimination and Excretion 105
4.3 Pharmacodynamics 108
4.3.1 Pharmacological Endpoint: Reduction of Target mRNA and Protein 109
4.3.2 Pharmacological Endpoint: Downstream Effects 113
4.3.3 Relationship between ASO Pharmacokinetics and Clinical Outcome 113
4.4 Summary 115
4.5 References 115
5 Pharmacokinetics of Viral and Non-Viral Gene Delivery Vectors
Martin Meyer, Gururaj Rao, Ke Ren, and Jeffrey Hughes 		121
5.1 General Overview of Gene Therapy 121
5.2 Anatomical Considerations 122
5.3 Naked DNA 122
5.4 Non-Viral Vectors 124
5.4.1 Polymer-Based Vectors 126
5.4.1.1 Introduction 126
5.4.1.2 Influence of Charge and Size 127
5.4.1.3 Biodistribution and Gene Expression 128
5.4.2 Lipid-Based Vectors 131
5.4.2.1 Introduction 131
5.4.2.2 Influence of Physico-Chemical Properties 133
5.4.2.3 Biodistribution and Gene Expression 134
5.5 Viral Vectors 136
5.5.1 rAAV: Properties 136
5.5.2 rAAV Serotype and Biodistribution 138
5.6 Summary 139
5.7 References 139
  Part III: Challenges and Opportunities  
6 Bioanalytical Methods Used for Pharmacokinetic Evaluations of Biotech Macromolecule Drugs: Issues, Assay Approaches, and Limitations
Jean W. Lee 		147
6.1 Introduction 147
6.2 Bioanalytical Methods for Macromolecule Drug Analysis: Common Considerations 148
6.2.1 Sample Integrity and Analyte Stability 148
6.2.2 Surface Adsorption 149
6.2.3 Process of Method Development and Validation of Bioanalytical Methods for Macromolecule Drug Analysis 150
6.2.4 Reference Standards 151
6.2.5 Drug Compounds that Exist Endogenously 152
6.2.6 Validation Samples, Quality Controls, and Assay Range 153
6.2.7 Protein Binding Problems 153
6.3 The Bioanalytical Method Workhorses 154
6.3.1 Ligand-Binding Assays: Immunoassays 157
6.3.1.1 Common Method Approach 157
6.3.1.2 Advantages of Immunoassays 158
6.3.1.3 Issues and Limitations of Immunoassays 158
6.3.2 HPLC-ESI-MS/MS Methods 162
6.3.2.1 Common Method Approach 162
6.3.2.2 Advantages of HPLC-ESI-MS/MS Methods 162
6.3.2.3 Issues and Limitations of LC-ESI-MS/MS Methods 162
6.4 Case Studies 167
6.4.1 Development and Validation of an ELISA Method for an Antibody Drug 167
6.4.2 Development and Validation of a Sandwich Immunoradiometric Method Using Commercial Kits for a Recombinant Peptide Drug 169
6.4.3 Development and Validation of LC-MS/MS Method for a Peptide Drug 171
6.5 Future Perspectives: Emerging Quantitative Methods 173
6.5.1 Sample Clean-Up 173
6.5.2 Innovations in MS Instruments 173
6.5.3 Quantification using Signature Hydrolytic Peptides 174
6.5.4 Advances in Ligand Reagents Design and Production 175
6.6 Conclusions 175
6.7 References 176
7 Limitations of Noncompartmental Pharmacokinetic Analysis of Biotech Drugs
Arthur B. Straughn 		181
7.1 Introduction 181
7.2 The Concept of Volume of Distribution 182
7.3 Calculation of Vss 183
7.4 Pitfalls in Calculating Vss 185
7.5 Results and Discussion 187
7.6 Conclusions 188
7.7 References 188
8 Bioequivalence of Biologics
Jeffrey S. Barrett 		189
8.1 Introduction 189
8.2 Prevailing Opinion: Science, Economics, and Politics 191
8.3 Biologics: Time Course of Immunogenicity 193
8.4 Pharmaceutical Equivalence 196
8.4.1 How Changes in Quality Might Affect Safety and Efficacy 197
8.5 Bioequivalence: Metrics and Methods for Biologics? 198
8.6 Case Study: Low-Molecular-Weight Heparins 200
8.7 Conclusions 205
8.8 References 206
9 Biopharmaceutical Challenges: Pulmonary Delivery of Proteins and Peptides
Kun Cheng and Ram I. Mahato 		209
9.1 Introduction 209
9.2 Structure and Physiology of the Pulmonary System 211
9.2.1 Airway Epithelium 212
9.2.2 Alveolar Epithelium 214
9.3 Barriers to Pulmonary Absorption of Peptides and Proteins 214
9.4 Strategies for Pulmonary Delivery 215
9.4.1 Intratracheal Instillation 215
9.4.2 Aerosol Inhalation 215
9.4.2.1 Aerosol Deposition Mechanisms 216
9.4.2.2 Devices for Pulmonary Drug Delivery 216
9.5 Experimental Models 220
9.5.1 Isolated Perfused Lung Model 220
9.5.2 Cell Culture Models 220
9.6 Pulmonary Delivery of Peptides and Proteins 221
9.6.1 Mechanisms of Peptide Absorption after Pulmonary Delivery 221
9.6.2 Mechanisms of Protein Absorption after Pulmonary Delivery 222
9.6.3 Pulmonary Delivery of Peptides and Proteins 223
9.6.3.1 Insulin 223
9.6.3.2 Salmon Calcitonin 227
9.6.3.3 Luteinizing Hormone-Releasing Hormone (LHRH) Agonists/Antagonists 229
9.6.3.4 Vasopressin 230
9.6.3.5 Granulocyte Colony-Stimulating Factor (G-CSF) 231
9.6.3.6 Interferons 232
9.6.3.7 TSH, FSH, and HCG 233
9.6.3.8 Elastase Inhibitors 233
9.7 Limitations of Aerosol Delivery 234
9.8 Summary 235
9.9 References 235
10 Biopharmaceutical Challenges: Delivery of Oligonucleotides
Lloyd G. Tillman and Gregory E. Hardee 		243
10.1 Introduction 243
10.2 ASOs: The Physico-Chemical Properties 244
10.3 Local Administration 246
10.3.1 Ocular Delivery 246
10.3.2 Local Gastrointestinal Delivery 247
10.3.2.1 Rectal Dosing 247
10.3.2.2 Oral Dosing 248
10.3.3 Pulmonary Delivery 249
10.3.3.1 Formulation Considerations 251
10.3.3.2 Deposition and Uptake 251
10.3.4 Delivery to the Brain 253
10.3.5 Topical Delivery 253
10.3.6 Other Local Delivery Approaches 254
10.4 Systemic Delivery 255
10.4.1 Parenteral Routes 255
10.4.1.1 Sustained-Release Subcutaneous Formulations 256
10.4.2 Oral Delivery 257
10.4.2.1 Permeability 258
10.4.2.2 Systemic Bioavailability 260
10.5 Conclusions 265
10.6 References 266
11 Custom-Tailored Pharmacokinetics and Pharmacodynamics via Chemical Modifications of Biotech Drugs
Francesco M. Veronese and Paolo Caliceti 		271
11.1 Introduction 271
11.2 Polymers Used in Biotechnological Drug PEGylation 272
11.3 Advantages of PEG as Drug Carrier 273
11.4 Chemical Aspects Critical for the Pharmacokinetics of Drug Conjugates 274
11.5 Insulin 279
11.6 Interferons 282
11.7 Avidin 285
11.8 Non-Peptide Drug Conjugation 288
11.8.1 Amphotericin B 289
11.8.2 Camptothecins 290
11.8.3 Cytosine Arabinoside (Ara-C) 291
11.9 Concluding Remarks 292
11.10 References 292
12 Exposure–Response Relationships for Therapeutic Biologic Products
Mohammad Tabrizi and Lorin K. Roskos 		295
12.1 Introduction 295
12.2 Overview of Pharmacokinetics and Pharmacodynamics 295
12.2.1 Pharmacokinetics 295
12.2.1.1 Absorption 296
12.2.1.2 Distribution 296
12.2.1.3 Elimination 296
12.2.1.4 Immunogenicity 298
12.2.2 Pharmacodynamics 298
12.3 Hormones 300
12.3.1 Insulin 301
12.3.2 Parathyroid Hormone 302
12.4 Cytokines 303
12.4.1 Interleukin-2 305
12.5 Growth Factors 306
12.5.1 Epoetin- 307
12.6 Soluble Receptors 308
12.6.1 Etanercept 308
12.7 Monoclonal Antibodies (mAbs) 310
12.7.1 Therapeutic Antibodies in Inflammatory Diseases 311
12.7.1.1 Anti-TNF- Antibodies 314
12.7.1.2 Efalizumab 316
12.7.1.3 Omalizumab 317
12.7.2 Therapeutic Antibodies in Oncology 317
12.7.2.1 Rituximab 318
12.7.2.2 Bevacizumab 319
12.7.2.3 Trastuzumab 320
12.8 Conclusions 321
12.9 References 321
  Part IV: Examples for the Integration of Pharmacokinetic and Pharmacodynamic Concepts Into the Biotech Drug Development Plan  
13 Preclinical and Clinical Drug Development of Tasidotin, a Depsi-Pentapeptide Oncolytic Agent
Peter L. Bonate, Larry Arthaud, and Katherine Stephenson 		331
13.1 Introduction 331
13.2 The Dolastatins 331
13.3 Discovery and Preclinical Pharmacokinetics of Tasidotin 333
13.4 Preclinical Pharmacology of Tasidotin and ILX651-C-Carboxylate 334
13.5 Toxicology of Tasidotin 334
13.6 Clinical Pharmacology and Studies of Tasidotin in Patients with Solid Tumors 335
13.7 Clinical Pharmacology of ILX651-C-Carboxylate 341
13.8 Exposure–Response Relationships 342
13.9 Discussion 343
13.10 Summary 349
13.11 References 349
14 Clinical Drug Development of Cetuximab, a Monoclonal Antibody
Arno Nolting, Floyd E. Fox, and Andreas Kovar 		353
14.1 Introduction 353
14.2 Specific Considerations in Oncologic Drug Development 354
14.3 Introduction to the Clinical Pharmacokinetics of Cetuximab 356
14.4 Early Attempts to Characterize the PK of Cetuximab 356
14.5 PK of Cetuximab Following Pooling of Data Across All Studies 357
14.5.1 Comparison of Single-Dose PK Parameters at Various Dose Levels 357
14.5.1.1 Maximum Serum Concentration 357
14.5.1.2 Area Under the Concentration-Time Curve 359
14.5.1.3 Clearance 360
14.5.1.4 Elimination Half-Life 361
14.5.1.5 Volume of Distribution 361
14.5.2 Drug Metabolism and in-vitro Drug–Drug Interaction Studies 362
14.5.3 Comparison of Single- and Multiple-Dose PK at the Approved Dosing Regimen 362
14.6 Characterization of Cetuximab PK by a Population PK Approach 364
14.7 Drug–Drug Interaction Studies 366
14.8 Conclusions 369
14.9 References 370
15 Integration of Pharmacokinetics and Pharmacodynamics Into the Drug Development of Pegfilgrastim, a Pegylated Protein
Bing-Bing Yang 		373
15.1 Introduction 373
15.2 Overview of Filgrastim Pharmacokinetics 374
15.3 The Making of Pegfilgrastim 375
15.4 Preclinical Pharmacokinetics and Pharmacodynamics of Pegfilgrastim 376
15.5 Pharmacokinetic and Pharmacodynamic Modeling 379
15.6 Clinical Pharmacokinetics and Pharmacodynamics of Pegfilgrastim 381
15.7 Basis for the Fixed-Dose Rationale 385
15.8 Clinical Evaluation of the Fixed Dose 389
15.9 Summary 391
15.10 References 391
  Subject Index 395

 
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