Full Description
With an emphasis on the fundamental and practical aspects of ADME for therapeutic proteins, this book helps readers strategize, plan and implement translational research for biologic drugs.
Details cutting-edge ADME (absorption, distribution, metabolism and excretion) and PKPD (pharmacokinetic / pharmacodynamics) modeling for biologic drugs
Combines theoretical with practical aspects of ADME in biologic drug discovery and development and compares innovator biologics with biosimilar biologics and small molecules with biologics, giving a lessons-learned perspective
Includes case studies about leveraging ADME to improve biologics drug development for monoclonal antibodies, fusion proteins, pegylated proteins, ADCs, bispecifics, and vaccines
Presents regulatory expectations and industry perspectives for developing biologic drugs in USA, EU, and Japan
Provides mechanistic insight into biodistribution and target-driven pharmacokinetics in important sites of action such as tumors and the brain
Contents
List of Contributors xvii
Foreword xix
1 ADME for Therapeutic Biologics: What Can We Leverage from Great Wealth of ADME Knowledge and Research for Small Molecules 1
Weirong Wang and Thomayant Prueksaritanont
1.1 Introduction 1
1.2 SM Drug Discovery and Development: Historical Perspective 1
1.3 LM Drug Discovery and Development 3
1.4 Conclusions 8
2 Protein Engineering: Applications to Therapeutic Proteins and Antibodies 13
Andrew G. Popplewell
2.1 Introduction 13
2.2 Methods of Protein Engineering 13
2.3 Applications of Protein Engineering to Non-Antibody Therapeutic Proteins 16
2.4 Applications of Protein Engineering to Therapeutic Antibodies 16
2.5 Future Perspectives 20
3 Therapeutic Antibodies—Protein Engineering to Influence ADME, PK, and Efficacy 25
Tatsuhiko Tachibana, Kenta Haraya, Yuki Iwayanagi and Tomoyuki Igawa
3.1 Introduction 25
3.2 Relationship between pI and Pharmacokinetics 26
3.3 Nonspecific/Specific Off]Target Binding 27
3.4 pH]Dependent Antigen Binding to Reduce Target]Mediated Elimination 28
3.5 Soluble Antigen Sweeping 31
3.6 Future Perspectives 34
4 ADME for Therapeutic Biologics: Antibody]Derived Proteins and Proteins with Novel Scaffolds 39
Chetan Rathi and Bernd Meibohm
4.1 Introduction 39
4.2 Antibody-Drug Conjugates 39
4.3 Bispecifics 45
4.4 Conclusions 50
5 Overview of ADME and PK/PD of ADCs 55
Baiteng Zhao and Tae H. Han
5.1 Introduction to ADC 55
5.2 Absorption 56
5.3 Distribution 58
5.4 Metabolism/Catabolism 58
5.5 Drug]Linker Stability 59
5.6 Elimination 60
5.7 Clinical PK 60
5.8 PK and PK/PD Modeling for ADCs 61
5.9 Summary 62
6 Role of Lymphatic System in Subcutaneous Absorption of Therapeutic Proteins 67
Jiunn H. Lin and Weirong Wang
6.1 Introduction 67
6.2 Physiology of Subcutaneous Tissue 68
6.3 Interstitial Transport from SC Injection Site 68
6.4 Relative Role of Blood and Lymphatic Systems in SC Absorption 69
6.5 Presystemic Catabolism in SC Absorption of Proteins 72
6.6 Effect of Injection Site on SC Absorption 74
6.7 Conclusions 74
7 Biodistribution of Therapeutic Biologics: Methods and Applications in Informing Target Biology, Pharmacokinetics, and Dosing Strategies 77
Sean B. Joseph, Saileta Prabhu and C. Andrew Boswell
7.1 Introduction 77
7.2 Determinants of Antibody Biodistribution 77
7.3 Methods of Measuring Antibody Biodistribution 81
7.4 Interpretation of Biodistribution Data 85
7.5 Concluding Remarks 87
8 Prediction of Human Pharmacokinetics for Protein]Based Biologic Therapeutics 91
Chao Han and Christina Lourdes Mayer
8.1 Introduction 91
8.2 General Allometric Scaling and Interspecies Scaling Methods 92
8.3 Considerations for Interspecies Scaling of Protein]Based Biologic Therapeutics 93
8.4 Physiologically Based PK Modeling 100
8.5 Perspectives Beyond the Prediction 101
8.6 Conclusions 102
9 Fixed Dosing versus Body]Size]Based Dosing for Therapeutic Biologics—A Clinical Pharmacology Strategy 107
Diane D. Wang, Justin T. Hoffman and Kourosh Parivar
9.1 Introduction 107
9.2 Conclusions 122
10 Impact of Diseases, Comorbidity, and Target Physiology on ADME, PK, and PK/PD of Therapeutic Biologics 125
Songmao Zheng, Weirong Wang and Honghui Zhou
10.1 Introduction 125
10.2 Impact of Diseases and Comorbidity on ADME and PK of Therapeutic Biologics 126
10.3 Impact of Disease and Target Physiology on PK and PK/PD of Therapeutic Biologics 130
10.4 Correlation between the PK of Therapeutic Biologics and Treatment Response 134
10.5 Other Patient Characteristics that can Impact the Treatment Response of Therapeutic Biologics 135
10.6 The Interplay between Disease, Target Physiology, and PK/PD of Therapeutic Biologics: Case Examples 136
10.7 Concluding Remarks 138
11 Immunogenicity: Its Impact on ADME of Therapeutic Biologics 147
Harald Kropshofer and Wolfgang F. Richter
11.1 Introduction 147
11.2 Immunogenicity of Therapeutic Biologics 147
11.3 Impact of ADA on ADME 150
11.4 How to Deal with ADME Consequences of Immune Responses? 155
11.5 Summary and Conclusions 156
12 Mechanistic Physiologically Based Pharmacokinetic Models in Development of Therapeutic Monoclonal Antibodies 159
Yanguang Cao and William J. Jusko
12.1 Background 159
12.2 History 159
12.3 Principles and Methods 162
12.4 Challenges 165
12.5 Simplified PBPK Models for mAbs 166
12.6 Perspectives 171
13 Integrated Quantitation of Biotherapeutic Drug-Target Binding, Biomarkers, and Clinical Response to Support Rational Dose Regimen Selection 175
Philip J. Lowe, Anne Kümmel, Christina Vasalou, Soichiro Matsushima and Andrej Skerjanec
13.1 Introduction 175
13.2 Methods 176
13.3 Results and Discussion 181
13.4 Conclusions 191
14 Target]Driven Pharmacokinetics of Biotherapeutics 197
Wilhelm Huisinga, Saskia Fuhrmann, Ludivine Fronton and Ben]Fillippo Krippendorff
14.1 Introduction 197
14.2 Soluble and Membrane]Bound Targets 197
14.3 Whole]Body Target]Mediated Drug Disposition Models and Their Approximations 198
14.4 Cell]Level Target]Mediated Drug Disposition Models 203
14.5 Simplified Physiologically Based Pharmacokinetic Model for mAbs 206
14.6 Conclusion: Looking at Data Through Models 209
15 Target]Driven Pharmacokinetics of Biotherapeutics 213
Guy M.L. Meno]Tetang
15.1 Introduction 213
15.2 Peptide-FC Fusion Proteins 214
15.3 Monoclonal Antibodies (mAbs) 215
15.4 Parameters Controlling Target]Driven Nonlinear Pharmacokinetics of Biotherapeutics 218
15.5 Impact of Target]Driven Nonlinear Pharmacokinetics of Biotherapeutics on Halometric Scaling 220
15.6 Conclusions and Perspectives 220
16 Tumor Effect]Site Pharmacokinetics: Mechanisms and Impact on Efficacy 225
Greg M. Thurber
16.1 Introduction 225
16.2 Tumor Pharmacokinetics 225
16.3 Impact of Tumor Pharmacokinetics on Efficacy 232
16.4 Conclusions 235
17 Brain Effect Site Pharmacokinetics: Delivery of Biologics Across the Blood-Brain Barrier 241
Gert Fricker and Anne Mahringer
17.1 Cytotic Processes at the BBB 243
17.2 Receptors at the BBB as Targets for Biologics 243
17.3 "Trojan Horse" Approaches to Target BBB Receptors 246
17.4 Colloidal Carriers for Drug Delivery 248
17.5 Other Brain]Directed Carriers 249
17.6 Stem Cell]Mediated Drug Delivery 250
17.7 Focused Ultrasound and Microbubbles 251
17.8 Conclusions and Perspectives 251
18 Molecular Pathology Techniques in the Preclinical Development of Therapeutic Biologics 257
Thierry Flandre, Sarah Taplin, Stewart Jones and Peter Lloyd
18.1 Introduction 257
18.2 Target Expression Profiling 259
18.3 Off]Target Binding of the Therapeutic Biologic Reagent 263
18.4 Biodistribution of Therapeutic Biologic Reagent 264
18.5 Discussion 265
18.6 Conclusion 267
19 Labeling and Imaging Techniques for Quantification of Therapeutic Biologics 271
Julie K. Jang, David Canter, Peisheng Hu, Alan L. Epstein and Leslie A. Khawli
19.1 Introduction 271
19.2 New and Conventional Methods for Labeling of Biologics 272
19.3 Molecular Imaging for the Study of PK and Biodistribution of Biologics 285
19.4 Conclusions and Perspectives 288
20 Knowledge of ADME of Therapeutic Proteins in Adults Facilitates Pediatric Development 295
Omoniyi J Adedokun and Zhenhua Xu
20.1 Introduction 295
20.2 Comparative Evaluation of ADME of Therapeutic Proteins between Adults and Children 296
20.3 Extrapolation of Efficacy from Adults to Pediatric Patients 298
20.4 Pediatric Dose Strategies 300
20.5 Sample]Size Determination for Pediatric Studies 304
20.6 Modeling and Simulation in Pediatric Drug Development Facilitated by Existing Adult Models 305
20.6.1 Modeling and Simulation Framework for Therapeutic Proteins in Pediatric Drug Development 305
20.6.2 Examples of the Application of Modeling and Simulation in the Development of Therapeutic Proteins in Pediatric Patients 307
20.7 Future Directions 309
21 LC/MS versus Immune]Based Bioanalytical Methods in Quantitation of Therapeutic Biologics in Biological Matrices 313
Bo An, Ming Zhang and Jun Qu
21.1 Introduction 313
21.2 Comparison of the Characteristics in Method Development 314
21.3 Comparison of Assay Performance 316
21.4 Application of LBA and LC/MS in the Analysis of Therapeutic Proteins 323
21.5 Summary and Future Perspective 324
22 Biosimilar Development: Nonclinical and Clinical Strategies and Challenges with a Focus on the Role of PK/PD Assessments 331
Susan Hurst and Donghua Yin
22.1 Introduction 331
22.2 Aspects of Biosimilarity 332
22.3 Biosimilars' Regulatory/Historical Perspective 333
22.4 Nonclinical Assessments in the Development of Biosimilars 336
22.5 Clinical PK and PD Assessments in the Development of Biosimilars 340
22.6 Concluding Remarks 344
23 ADME Processes in Vaccines and PK/PD Approaches for Vaccination Optimization 347
José David Gómez]Mantilla, Iñaki F. Trocóniz and María J. Garrido
23.1 Introduction 347
23.2 Biopharmaceutic Considerations on Vaccine ADME Processes 350
23.3 Vaccines and ADME Processes 350
23.4 Mathematical Modeling for Vaccine Optimization in Cancer Treatment 360
23.5 Systems Vaccinology: Application of Systems Biology in Personalized Vaccination 362
23.6 Concluding Remarks 363
24 Drug Development Strategies for Therapeutic Biologics: Industry Perspectives 369
Theresa Yuraszeck and Megan Gibbs
24.1 Introduction 369
24.2 Preclinical Development 372
24.3 Clinical Development 375
24.4 Biosimilars 377
24.5 Emerging Markets 377
24.6 Conclusions 378
25 Review: The Critical Role of Clinical Pharmacology in the Development of Biologics 385
Liang Zhao, Diane Wang, Ping Zhao, Elizabeth Y. Shang, Yaning Wang and Vikram Sinha
25.1 Introduction 385
25.2 PK and PD of Biologics 385
25.3 Critical Role of Clinical Pharmacology and Related Regulatory Guidance for Biologics Development 387
25.4 Model]Based Drug Development for Biologics 393
25.5 Conclusions 397
25.6 Disclaimer 397
26 Investigating the Nonclinical ADME and PK/PD of an Antibody-Drug Conjugate: A Case Study of ADO]Trastuzumab Emtansine (T]DM1) 401
Jay Tibbitts
26.1 Introduction 401
26.2 Importance of ADME for ADCs 402
26.3 T]DM1 Bioanalytical Strategy and Methods 403
26.4 Ex Vivo Linker Stability 404
26.5 Plasma PK 404
26.6 Distribution of T]DM1 406
26.7 T]DM1 Catabolism and Elimination 406
26.8 T]DM1 Nonclinical PK/PD 408
26.9 Conclusions 409
27 Use of PK/PD Knowledge in Guiding Bispecific Biologics Research and Development 413
Andreas Baumann, Saileta Prabhu and Jitendra Kanodia
27.1 Introduction 413
27.2 Structural Formats and Generation of Bispecific Biologics 415
27.3 Biochemistry and Pharmacology of Bispecifics 416
27.4 Pharmacokinetics 416
27.5 Pharmacokinetic-Pharmacodynamic Model]Informed Design of bsAbs 418
27.6 Application of PK/PD in the Research and Development of Bispecific Biologics: Case Examples 419
27.7 Outlook 421
References 422
Index 427
