ADME and Translational Pharmacokinetics / Pharmacodynamics of Therapeutic Proteins

Honghui Zhou is a Senior Director and Janssen Fellow, at Janssen Research & Development, LLC and US head of Pharmacological and Translational Modeling. Board-certified by the American Board of Clinical Pharmacology and a Fellow of American Association of Pharmaceutical Scientists (AAPS) and American College of Clinical Pharmacology (ACCP), he has authored 200 peer-reviewed scientific papers, book chapters, and conference abstracts and co-edited the book Drug-Drug Interactions for Therapeutic Biologics (Wiley, 2013). Frank-Peter Theil heads nonclinical development at UCB Biopharma. Dr. Theil has authored and co-authored 40 research publications, three book chapters and he has given numerous invited presentations at national and international scientific meetings. He is a member of the American Association of Pharmaceutical Scientists (AAPS) and American Society of Clinical Pharmacology and Therapeutics (ASCPT).

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

1.2.1 Evolving Role of DMPK: Paradigm Shift 1

1.2.2 Key Enablers to Successful DMPK Support 2

1.2.3 Regulatory Considerations 3

1.3 LM Drug Discovery and Development 3

1.3.1 Role of DMPK: Current State 3

1.3.2 SM/LM DMPK Analogy 4

1.3.3 Leveraging SM Experience: Case Examples 6

1.4 Conclusions 8

References 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

2.2.1 General Techniques 13

2.2.2 Introducing Specific, Directed Sequence Changes 14

2.2.3 Fragment Fusion 14

2.2.4 Gene Synthesis 14

2.2.5 Molecular “Evolution” through Display and Selection 14

2.3 Applications of Protein Engineering to Non-Antibody Therapeutic Proteins 16

2.4 Applications of Protein Engineering to Therapeutic Antibodies 16

2.4.1 Reduction of Immunogenicity 17

2.4.2 Improving Stability and Biophysical Properties 17

2.4.3 Tailoring Mechanism of Action 19

2.4.4 Influencing Distribution and PK 19

2.4.5 Improving Ligand/Receptor Interaction 20

2.5 Future Perspectives 20

References 21

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

3.2.1 pI and Clearance 26

3.2.2 pI and Distribution 26

3.2.3 pI and SC Absorption 27

3.2.4 pI and FcRn Function 27

3.3 Nonspecific/Specific Off‐Target Binding 27

3.3.1 Nonspecific Binding and Clearance 27

3.3.2 Specific Off‐Target Binding and Clearance 28

3.4 pH‐Dependent Antigen Binding to Reduce Target‐Mediated Elimination 28

3.4.1 Concept of Recycling Antibody 28

3.4.2 pH Dependency and Target‐Mediated Elimination 29

3.5 Soluble Antigen Sweeping 31

3.5.1 Concept of Sweeping Antibody 31

3.5.2 FcRn‐Mediated Sweeping 31

3.5.3 FcγRIIb‐Mediated Sweeping 33

3.6 Future Perspectives 34

References 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

4.2.1 Components of ADCs 40

4.2.2 Types of ADC Analytes and Their PK Interpretation 41

4.2.3 PK of ADC 42

4.2.4 Immunogenicity of ADC 45

4.2.5 Exposure–Response of ADCs 45

4.2.6 Dose‐Dependent PK of ADCs 45

4.3 Bispecifics 45

4.3.1 Bispecific Antibody Formats 46

4.3.2 PK of Bispecific Constructs 47

4.3.3 Immunogenicity of Bispecific Constructs 48

4.3.4 Examples of Bispecific Therapeutics—Oncology Indications 48

4.3.5 Examples of Bispecific Therapeutics—CNS Indications 49

4.3.6 Examples of Bispecific Therapeutics—Ocular Indications 49

4.4 Conclusions 50

References 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

References 63

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

References 75

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

7.2.1 Molecular Properties 78

7.2.2 Physiological (Tissue) Properties 79

7.3 Methods of Measuring Antibody Biodistribution 81

7.3.1 In Vivo Study Design Considerations 81

7.3.2 Tissue Analysis 85

7.4 Interpretation of Biodistribution Data 85

7.4.1 Calculations and Units 86

7.4.2 Compartmental Tissue Concentrations 86

7.4.3 Blood Correction 86

7.4.4 Derivation of Interstitial Concentrations 87

7.4.5 Confirmation of Receptor Occupancy 87

7.4.6 Explaining Unexpectedly Rapid Clearance 87

7.4.7 Assisting in Clinical Dose Selection 87

7.5 Concluding Remarks 87

Acknowledgments 88

References 88

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

8.3.1 Considerations for Interspecies Scaling of mAbs 95

8.3.2 Other Factors that may Affect PK Interspecies Scaling for Protein‐Based Therapeutics 98

8.4 Physiologically Based PK Modeling 100

8.5 Perspectives Beyond the Prediction 101

8.5.1 Prediction of Human PK Serves Different Purposes at Different Stages of Drug Development 101

8.5.2 Safety Considerations When Predicting Human PK for Protein‐Based Therapeutics 102

8.6 Conclusions 102

References 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

9.1.1 Considerations for the Selection of a Dosing Approach 108

9.1.2 Evaluations of Fixed Dosing versus Body‐Size‐Based Dosing 110

9.1.3 Rationale Dosing Approach Selection Strategies Based on Stage of Clinical Development 121

9.2 Conclusions 122

References 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

10.1.1 ADME of Biologics 125

10.1.2 Roles of TMDD for Biologics 126

10.2 Impact of Diseases and Comorbidity on ADME and PK of Therapeutic Biologics 126

10.2.1 Disease and Comorbidity on the Subcutaneous Absorption of Biologics 126

10.2.2 Disease and Comorbidity on the Distribution of Biologics 127

10.2.3 Hepatic Impairment 128

10.2.4 Renal Impairment 128

10.2.5 Immune‐Mediated Inflammatory Diseases 129

10.2.6 Diabetes 129

10.2.7 Immunogenicity 130

10.3 Impact of Disease and Target Physiology on PK and PK/PD of Therapeutic Biologics 130

10.3.1 Biologics against Membrane‐Bound Targets 130

10.3.2 Biologics against Soluble Targets 133

10.3.3 When Targets Exist as Both Membrane‐Bound and Soluble 133

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

Acknowledgments 138

References 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

11.2.1 The Underlying Cellular Immunology 147

11.2.2 Aspects Facilitating Immune Responses against Biologics 149

11.3 Impact of ADA on ADME 150

11.3.1 Impact of ADA on Bioanalytical Results 150

11.3.2 Formation of Immune Complexes 150

11.3.3 Clearance of Immune Complexes 151

11.3.4 Sustaining and Clearing ADAs 153

11.3.5 Impact of ADAs on Distribution 155

11.3.6 Impact of ADAs on Absorption 155

11.4 How to Deal with ADME Consequences of Immune Responses? 155

11.4.1 PK Assessment in the Presence of ADAs 155

11.4.2 In‐Study Options to Overcome ADA Formation 156

11.5 Summary and Conclusions 156

References 157

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

12.4.1 Physiological Parameters 165

12.4.2 Extravasation Mechanisms 165

12.4.3 FcRn Function 165

12.5 Simplified PBPK Models for mAbs 166

12.5.1 Minimal PBPK Models 166

12.5.2 Survey of mAb PK in Humans with the Minimal PBPK Model 168

12.5.3 Minimal PBPK Model with Target‐Mediated Drug Disposition 169

12.6 Perspectives 171

Acknowledgments 172

References 172

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

13.2.1 Omalizumab, IgE, Itch, and Hives 176

13.2.2 QGE031 and Omalizumab, IgE, Basophil FcεR1 and Surface IgE, and Allergen Skin Prick Test Response 178

13.2.3 Common Components 180            

13.3 Results and Discussion 181

13.3.1 Omalizumab Capture of IgE Reducing Itch and Hives 181

13.3.2 QGE031 and Omalizumab Capture of IgE, Reducing Basophil FcεR1, Surface IgE, and Allergen Skin Reactivity 185

13.4 Conclusions 191

Acknowledgments 193

References 193

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

14.3.1 Generic Whole‐Body TMDD Model 198

14.3.2 Characteristics of Target‐Driven PK Profiles 199

14.3.3 Location of the Target: Central versus Peripheral Compartment 200

14.3.4 Parameter Identifiability and Model Reduction 200

14.3.5 Extended Michaelis–Menten Approximation with Target Turnover 201

14.3.6 Michaelis–Menten Approximation with Target Turnover 202

14.3.7 Extended Michaelis–Menten Approximation 202

14.3.8 Michaelis–Menten Approximation 203

14.3.9 Model Selection 203

14.4 Cell‐Level Target‐Mediated Drug Disposition Models 203

14.4.1 Cell‐Level TMDD Model with a Single‐Cell Type 204

14.4.2 Cell‐Level TMDD Model with Normal and Tumor Cells 204

14.5 Simplified Physiologically Based Pharmacokinetic Model for mAbs 206

14.5.1 Target‐Independent Pharmacokinetics 206

14.5.2 Drug–Target Interaction 208

14.6 Conclusion: Looking at Data Through Models 209

Acknowledgment 209

References 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

15.3.1 Antibodies Absorption 215

15.3.2 Antibodies Distribution 215

15.3.3 Mechanism of mAb Elimination 216

15.3.4 Antibody–Drug Conjugates 217

15.3.5 Recombinant Proteins 218

15.4 Parameters Controlling Target‐Driven Nonlinear Pharmacokinetics of Biotherapeutics 218

15.4.1 Target Localization 218

15.4.2 Target Affinity 219

15.4.3 Target Turnover 219

15.4.4 Target Baseline and Disease Progression 219

15.4.5 Off‐Target Binding 220

15.5 Impact of Target‐Driven Nonlinear Pharmacokinetics of Biotherapeutics on Halometric Scaling 220

15.5.1 Ethnic Differences 220

15.6 Conclusions and Perspectives 220

References 221

16 Tumor Effect‐Site Pharmacokinetics: Mechanisms and Impact on Efficacy 225
Greg M. Thurber

16.1 Introduction 225

16.2 Tumor Pharmacokinetics 225

16.2.1 Tissue Physiology, Fluid Balance, and Macromolecular Transport 225

16.2.2 Tumor Transport—An Overview 226

16.2.3 Mechanisms of Tumor Transport 227

16.2.4 Revisiting Tumor Transport Theory 229

16.2.5 Impact of Drug Targeting Parameters on Distribution 231

16.2.6 Experimental Validation and Comparison with Small Molecules 232

16.3 Impact of Tumor Pharmacokinetics on Efficacy 232

16.3.1 Overview of Cell‐Killing Mechanisms 232

16.3.2 Pharmacokinetic Impact on Efficacy 233

16.4 Conclusions 235

References 236

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

17.2.1 Transferrin Receptor 243

17.2.2 Insulin Receptor 244

17.2.3 Insulin‐Like Growth Factor Receptor 244

17.2.4 LDL Receptor 244

17.2.5 Low Density Lipoprotein Receptor‐Related Protein 1 245

17.2.6 Low Density Lipoprotein Receptor‐Related Protein 2 245

17.2.7 Leptin Receptor (OBR) 245

17.2.8 Receptor of Advanced Glycation Endproducts 245

17.2.9 Scavenger Receptor(SR) 246

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

References 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

18.2.1 Detection of DNA/RNA‐Based Target Expression Using Whole Tissue Extracts 259

18.2.2 Detection of Protein‐Based Target Expression Using Whole Tissue Extracts 260

18.2.3 Localization of DNA/RNA and Protein‐Based Target Expression at the Cellular Level Using Tissue Sections 262

18.3 Off‐Target Binding of the Therapeutic Biologic Reagent 263

18.3.1 Tissue Cross‐Reactivity Study 263

18.3.2 Protein Microarray 264

18.3.3 Cell Microarray Technology (Retrogenix) 264

18.3.4 Protein Pull‐Down Assays 264

18.4 Biodistribution of Therapeutic Biologic Reagent 264

18.4.1 Whole‐Body Autoradiography 264

18.4.2 Biodistribution: Immunohistochemistry Methods for Protein‐Based Therapeutic Products 265

18.4.3 Biodistribution: Quantitative PCR Methods DNA/RNA‐Based Therapeutic Products 265

18.5 Discussion 265

18.5.1 Considerations in the Interpretation of Molecular Pathology‐Based Data 265

18.5.2 Examples of Molecular Pathology Methods Used in Preclinical Development 266

18.6 Conclusion 267

References 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

19.2.1 Choice of Labels 272

19.2.2 Labeling Strategies of Biologics 277

19.3 Molecular Imaging for the Study of PK and Biodistribution of Biologics 285

19.3.1 SPECT Imaging 286

19.3.2 PET Imaging 286

19.3.3 Optical Imaging 288

19.4 Conclusions and Perspectives 288

References 289

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

20.2.1 Absorption 296

20.2.2 Distribution 297

20.2.3 Metabolism and Elimination 297

20.3 Extrapolation of Efficacy from Adults to Pediatric Patients 298

20.3.1 No Extrapolation Approach 298

20.3.2 Partial Extrapolation Approach 298

20.3.3 Full Extrapolation Approach 299

20.4 Pediatric Dose Strategies 300

20.4.1 Body Weight‐Based (Linear) Dose‐Adjustment Approach 300

20.4.2 BSA‐Based (Linear) Dose‐Adjustment Approach 304

20.4.3 Tiered‐Fixed Dose‐Adjustment Approach 304

20.4.4 Hybrid Dose‐Adjustment Approach 304

20.4.5 Other Dose‐Adjustment Approaches 304

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

References 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

21.2.1 Method Development Time 314

21.2.2 Specificity 314

21.2.3 Characteristics of Method Development 314

21.3 Comparison of Assay Performance 316

21.3.1 Sample Preparation 316

21.3.2 Calibration Curve and Linearity Range 318

21.3.3 Applicability 318

21.3.4 Accuracy 319

21.3.5 Sensitivity 319

21.3.6 Reproducibility 321

21.4 Application of LBA and LC/MS in the Analysis of Therapeutic Proteins 323

21.4.1 Quantification of mAb in Plasma and Tissues 323

21.4.2 Application in Multiplexed Analysis 323

21.4.3 Characterization of Antibody–Drug Conjugates (ADC) 324

21.5 Summary and Future Perspective 324

References 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

22.3.1 European Union 333

22.3.2 EMA Nonclinical In Vivo Considerations 333

22.3.3 EMA Clinical Considerations (Related to PK/PD) 334

22.3.4 United States 334

22.3.5 FDA Nonclinical In Vivo Considerations 335

22.3.6 FDA Clinical Considerations (Related to PK/PD) 335

22.3.7 The WHO and Other Global Markets 336

22.4 Nonclinical Assessments in the Development of Biosimilars 336

22.4.1 Biosimilars Nonclinical Development 336

22.4.2 Designing the Nonclinical In Vivo Study 336

22.4.3 Designing the Nonclinical Study: Immunogenicity/Bioanalytical 337

22.4.4 Designing the Nonclinical In Vivo Study—PK and PD Focus 337

22.4.5 Designing the Nonclinical In Vivo Study—No Relevant Nonclinical Species 338

22.5 Clinical PK and PD Assessments in the Development of Biosimilars 340

22.5.1 Biosimilars Clinical Development 340

22.5.2 Bioanalytical Assays for Biosimilars PK and PD Investigations 341

22.5.3 Design Considerations for Phase I PK and PD Similarity Studies 341

22.5.4 PK Similarity Study of PF‐05280014, a Proposed Biosimilar to Trastuzumab: An Example 342

22.5.5 Extrapolation of Clinical Data 342

22.6 Concluding Remarks 344

Acknowledgments 344

References 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

23.1.1 Vaccine Development 347

23.1.2 Types of Vaccines 348

23.1.3 Basic Immunological Mechanism of Vaccine Development 348

23.2 Biopharmaceutic Considerations on Vaccine ADME Processes 350

23.3 Vaccines and ADME Processes 350

23.3.1 Effect of Vaccine Formulation on ADME 351

23.3.2 Effect of Route of Administration 353

23.3.3 Metabolism and Excretion 357

23.3.4 PK Considerations 357

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

References 363

24 Drug Development Strategies for Therapeutic Biologics: Industry Perspectives 369
Theresa Yuraszeck and Megan Gibbs

24.1 Introduction 369

24.1.1 Biologics Properties and Classification 370

24.1.2 Assay Development and Validation 372

24.2 Preclinical Development 372

24.2.1 FIH Starting Dose 374

24.3 Clinical Development 375

24.3.1 Intrinsic and Extrinsic Factors 375

24.3.2 Special Populations: Renal and Hepatic Impairment 376

24.3.3 Special Populations: Pediatrics 376

24.4 Biosimilars 377

24.5 Emerging Markets 377

24.6 Conclusions 378

References 379

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

25.2.1 Structural Difference between SMDs and Biological Products 385

25.2.2 Route of Administration and Absorption 386

25.2.3 Distribution 386

25.2.4 Metabolism and Elimination 386

25.2.5 mAb Distribution 386

25.2.6 Catabolism and Elimination 387

25.2.7 Other Biologics 387

25.3 Critical Role of Clinical Pharmacology and Related Regulatory Guidance for Biologics Development 387

25.3.1 First‐in‐Human (FIH) Dose Determination and Study Design 387

25.3.2 Critical Considerations from a Standpoint of Clinical Pharmacology in Biologics Development 388

25.4 Model‐Based Drug Development for Biologics 393

25.4.1 Fixed Dosing versus Body Size‐Adjusted Dosing 394

25.4.2 Mechanism‐ and Physiologically Based Models for mAbs 394

25.4.3 Utility of Meta‐Analysis 395

25.4.4 Utility of Case–Control Analysis in Biologics Development 396

25.5 Conclusions 397

25.6 Disclaimer 397

References 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

References 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

27.3.1 Affinity 416

27.3.2 Avidity 416

27.4 Pharmacokinetics 416

27.4.1 PK Assay Strategies Employed for the Development of bsAbs 417

27.4.2 Immunogenicity Strategies Employed for the Development of bsAbs 418

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

27.6.1 Anti‐TfR/BACE1 to Improve Therapeutic Antibody Transport across the Blood–Brain Barrier 419

27.6.2 PK Characterization to Optimize bsAb Molecule Design and Selection for Ophthalmology 420

27.6.3 Pharmacokinetic Studies during Development of a Bispecific T‐Cell Engager 421

27.7 Outlook 421

References 422

Index 427