Foreword ................................................... V
Preface .................................................. VII
List of Contributors ..................................... XIX
Part I: Introduction
1 The Role of Pharmacokinetics and Pharmacodynamics in
the Development of Biotech Drugs ........................... 3
Bernd Meibohm
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 ................. 17
Lisa Tang and Bernd Meibohm
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 ................. 45
Katharina Kuester and Charlotte Klofi
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
3.5 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 Fe 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 Drag 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 .......................................... 93
Rosie Z. Yu, Richard S. Geary, and Arthur A. Levin
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 ......................... 205
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 .................................................. 121
Martin Meyer, Cururaj Rao, Ke Ren, and Jeffrey Hughes
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 ........................ 247
Jean W. Lee
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 Drag .................... 169
6.4.3 Development and Validation of LC-MS/MS Method
for a Peptide Drag ................................ 172
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 ................................ 182
Arthur B. Straughn
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 Biologies .............................. 289
Jeffrey S. Barrett
8.1 Introduction ............................................. 189
8.2 Prevailing Opinion: Science, Economics, and Politics ..... 191
8.3 Biologies: 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 Biologies? ....... 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 .................................... 209
Кип Cheng and Ram I. Mahato
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 ............ 226
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 ......................................... 243
Lloyd C. Tillman and Gregory E. Hardee
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 .................... 252
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 .............. 272
Francesco M. Veronese and Paolo Caliceti
11.1 Introduction ............................................. 272
11.2 Polymers Used in Biotechnological Drag 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 В .................................... 289
11.8.2 Camptothecins ..................................... 290
11.8.3 Cytosine Arabinoside (Ara-C) ...................... 292
11.9 Concluding Remarks ....................................... 292
11.10 References .............................................. 292
12 Exposure-Response Relationships for Therapeutic Biologic
Products ................................................. 295
Mohammad Tabrizi and Lorin K. Roskos
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-oc ........................................ 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-a 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 .............................. 329
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 ..................... 331
Peter L. Bonate, Larry Arthaud, and Katherine
Stephenson
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 ................................................. 353
Arno Nolt'mg, Floyd E. Fox, and Andreas Kovar
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 .................... 362
14.5.1.5 Volume of Distribution ................... 362
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-Drag 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 .................................................. 373
Bing-Bing Yang
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 .............................................. 392
Subject Index ............................................ 395
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