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).

"At the outset, one�s impressed with the scope of the book; it provides an outline of very diverse topics starting with the basics of protein engineering and how these are used to design and manipulate the ADME properties of recombinant and synthetic proteins...The authors have to be congratulated on their endeavor to stitch these topics together in a single book...With such a wide range of topics, even an experienced scientific practitioner in this area is likely to find something new to engage them and expand their knowledge...In summary, an excellent and comprehensive book for beginners to the CP/PK area to acquaint themselves with the area of biologics (specifically mAb) CP/PKPD principles and for experienced CP/PK scientists for reference." (CPT: Pharmacometrics & Systems Pharmacology, March 2017)

• List of Contributors xviiForeword xix1 ADME for Therapeutic Biologics: What Can We Leverage from Great Wealth of ADME Knowledge and Research for Small Molecules 1Weirong Wang and Thomayant Prueksaritanont1.1 Introduction 11.2 SM Drug Discovery and Development: Historical Perspective 11.3 LM Drug Discovery and Development 31.4 Conclusions 82 Protein Engineering: Applications to Therapeutic Proteins and Antibodies 13Andrew G. Popplewell2.1 Introduction 132.2 Methods of Protein Engineering 132.3 Applications of Protein Engineering to Non-Antibody Therapeutic Proteins 162.4 Applications of Protein Engineering to Therapeutic Antibodies 162.5 Future Perspectives 203 Therapeutic Antibodies—Protein Engineering to Influence ADME, PK, and Efficacy 25Tatsuhiko Tachibana, Kenta Haraya, Yuki Iwayanagi and Tomoyuki Igawa3.1 Introduction 253.2 Relationship between pI and Pharmacokinetics 263.3 Nonspecific/Specific Off]Target Binding 273.4 pH]Dependent Antigen Binding to Reduce Target]Mediated Elimination 283.5 Soluble Antigen Sweeping 313.6 Future Perspectives 344 ADME for Therapeutic Biologics: Antibody]Derived Proteins and Proteins with Novel Scaffolds 39Chetan Rathi and Bernd Meibohm4.1 Introduction 394.2 Antibody–Drug Conjugates 394.3 Bispecifics 454.4 Conclusions 505 Overview of ADME and PK/PD of ADCs 55Baiteng Zhao and Tae H. Han5.1 Introduction to ADC 555.2 Absorption 565.3 Distribution 585.4 Metabolism/Catabolism 585.5 Drug]Linker Stability 595.6 Elimination 605.7 Clinical PK 605.8 PK and PK/PD Modeling for ADCs 615.9 Summary 626 Role of Lymphatic System in Subcutaneous Absorption of Therapeutic Proteins 67Jiunn H. Lin and Weirong Wang6.1 Introduction 676.2 Physiology of Subcutaneous Tissue 686.3 Interstitial Transport from SC Injection Site 686.4 Relative Role of Blood and Lymphatic Systems in SC Absorption 696.5 Presystemic Catabolism in SC Absorption of Proteins 726.6 Effect of Injection Site on SC Absorption 746.7 Conclusions 747 Biodistribution of Therapeutic Biologics: Methods and Applications in Informing Target Biology, Pharmacokinetics, and Dosing Strategies 77Sean B. Joseph, Saileta Prabhu and C. Andrew Boswell7.1 Introduction 777.2 Determinants of Antibody Biodistribution 777.3 Methods of Measuring Antibody Biodistribution 817.4 Interpretation of Biodistribution Data 857.5 Concluding Remarks 878 Prediction of Human Pharmacokinetics for Protein]Based Biologic Therapeutics 91Chao Han and Christina Lourdes Mayer8.1 Introduction 918.2 General Allometric Scaling and Interspecies Scaling Methods 928.3 Considerations for Interspecies Scaling of Protein]Based Biologic Therapeutics 938.4 Physiologically Based PK Modeling 1008.5 Perspectives Beyond the Prediction 1018.6 Conclusions 1029 Fixed Dosing versus Body]Size]Based Dosing for Therapeutic Biologics—A Clinical Pharmacology Strategy 107Diane D. Wang, Justin T. Hoffman and Kourosh Parivar9.1 Introduction 1079.2 Conclusions 12210 Impact of Diseases, Comorbidity, and Target Physiology on ADME, PK, and PK/PD of Therapeutic Biologics 125Songmao Zheng, Weirong Wang and Honghui Zhou10.1 Introduction 12510.2 Impact of Diseases and Comorbidity on ADME and PK of Therapeutic Biologics 12610.3 Impact of Disease and Target Physiology on PK and PK/PD of Therapeutic Biologics 13010.4 Correlation between the PK of Therapeutic Biologics and Treatment Response 13410.5 Other Patient Characteristics that can Impact the Treatment Response of Therapeutic Biologics 13510.6 The Interplay between Disease, Target Physiology, and PK/PD of Therapeutic Biologics: Case Examples 13610.7 Concluding Remarks 13811 Immunogenicity: Its Impact on ADME of Therapeutic Biologics 147Harald Kropshofer and Wolfgang F. Richter11.1 Introduction 14711.2 Immunogenicity of Therapeutic Biologics 14711.3 Impact of ADA on ADME 15011.4 How to Deal with ADME Consequences of Immune Responses? 15511.5 Summary and Conclusions 15612 Mechanistic Physiologically Based Pharmacokinetic Models in Development of Therapeutic Monoclonal Antibodies 159Yanguang Cao and William J. Jusko12.1 Background 15912.2 History 15912.3 Principles and Methods       16212.4 Challenges 16512.5 Simplified PBPK Models for mAbs 16612.6 Perspectives 17113 Integrated Quantitation of Biotherapeutic Drug–Target Binding, Biomarkers, and Clinical Response to Support Rational Dose Regimen Selection 175Philip J. Lowe, Anne Kümmel, Christina Vasalou, Soichiro Matsushima and Andrej Skerjanec13.1 Introduction 17513.2 Methods 17613.3 Results and Discussion 18113.4 Conclusions 19114 Target]Driven Pharmacokinetics of Biotherapeutics 197Wilhelm Huisinga, Saskia Fuhrmann, Ludivine Fronton and Ben]Fillippo Krippendorff14.1 Introduction 19714.2 Soluble and Membrane]Bound Targets 19714.3 Whole]Body Target]Mediated Drug Disposition Models and Their Approximations 19814.4 Cell]Level Target]Mediated Drug Disposition Models 20314.5 Simplified Physiologically Based Pharmacokinetic Model for mAbs 20614.6 Conclusion: Looking at Data Through Models 20915 Target]Driven Pharmacokinetics of Biotherapeutics 213Guy M.L. Meno]Tetang15.1 Introduction 21315.2 Peptide–FC Fusion Proteins 21415.3 Monoclonal Antibodies (mAbs) 21515.4 Parameters Controlling Target]Driven Nonlinear Pharmacokinetics of Biotherapeutics 21815.5 Impact of Target]Driven Nonlinear Pharmacokinetics of Biotherapeutics on Halometric Scaling 22015.6 Conclusions and Perspectives 22016 Tumor Effect]Site Pharmacokinetics: Mechanisms and Impact on Efficacy 225Greg M. Thurber16.1 Introduction 22516.2 Tumor Pharmacokinetics 22516.3 Impact of Tumor Pharmacokinetics on Efficacy 23216.4 Conclusions 23517 Brain Effect Site Pharmacokinetics: Delivery of Biologics Across the Blood–Brain Barrier 241Gert Fricker and Anne Mahringer17.1 Cytotic Processes at the BBB 24317.2 Receptors at the BBB as Targets for Biologics 24317.3 "Trojan Horse" Approaches to Target BBB Receptors 24617.4 Colloidal Carriers for Drug Delivery 24817.5 Other Brain]Directed Carriers 24917.6 Stem Cell]Mediated Drug Delivery 25017.7 Focused Ultrasound and Microbubbles 25117.8 Conclusions and Perspectives 25118 Molecular Pathology Techniques in the Preclinical Development of Therapeutic Biologics 257Thierry Flandre, Sarah Taplin, Stewart Jones and Peter Lloyd18.1 Introduction 25718.2 Target Expression Profiling 25918.3 Off]Target Binding of the Therapeutic Biologic Reagent 26318.4 Biodistribution of Therapeutic Biologic Reagent 26418.5 Discussion 26518.6 Conclusion 26719 Labeling and Imaging Techniques for Quantification of Therapeutic Biologics 271Julie K. Jang, David Canter, Peisheng Hu, Alan L. Epstein and Leslie A. Khawli19.1 Introduction 27119.2 New and Conventional Methods for Labeling of Biologics 27219.3 Molecular Imaging for the Study of PK and Biodistribution of Biologics 28519.4 Conclusions and Perspectives 28820 Knowledge of ADME of Therapeutic Proteins in Adults Facilitates Pediatric Development 295Omoniyi J Adedokun and Zhenhua Xu20.1 Introduction 29520.2 Comparative Evaluation of ADME of Therapeutic Proteins between Adults and Children 29620.3 Extrapolation of Efficacy from Adults to Pediatric Patients 29820.4 Pediatric Dose Strategies 30020.5 Sample]Size Determination for Pediatric Studies 30420.6 Modeling and Simulation in Pediatric Drug Development Facilitated by Existing Adult Models 30520.6.1 Modeling and Simulation Framework for Therapeutic Proteins in Pediatric Drug Development 30520.6.2 Examples of the Application of Modeling and Simulation in the Development of Therapeutic Proteins in Pediatric Patients 30720.7 Future Directions 30921 LC/MS versus Immune]Based Bioanalytical Methods in Quantitation of Therapeutic Biologics in Biological Matrices 313Bo An, Ming Zhang and Jun Qu21.1 Introduction 31321.2 Comparison of the Characteristics in Method Development 31421.3 Comparison of Assay Performance 31621.4 Application of LBA and LC/MS in the Analysis of Therapeutic Proteins 32321.5 Summary and Future Perspective 32422 Biosimilar Development: Nonclinical and Clinical Strategies and Challenges with a Focus on the Role of PK/PD Assessments 331Susan Hurst and Donghua Yin22.1 Introduction 33122.2 Aspects of Biosimilarity 33222.3 Biosimilars’ Regulatory/Historical Perspective 33322.4 Nonclinical Assessments in the Development of Biosimilars 33622.5 Clinical PK and PD Assessments in the Development of Biosimilars 34022.6 Concluding Remarks 34423 ADME Processes in Vaccines and PK/PD Approaches for Vaccination Optimization 347José David Gómez]Mantilla, Iñaki F. Trocóniz and María J. Garrido23.1 Introduction 34723.2 Biopharmaceutic Considerations on Vaccine ADME Processes 35023.3 Vaccines and ADME Processes 35023.4 Mathematical Modeling for Vaccine Optimization in Cancer Treatment 36023.5 Systems Vaccinology: Application of Systems Biology in Personalized Vaccination 36223.6 Concluding Remarks 36324 Drug Development Strategies for Therapeutic Biologics: Industry Perspectives 369Theresa Yuraszeck and Megan Gibbs24.1 Introduction 36924.2 Preclinical Development 37224.3 Clinical Development 37524.4 Biosimilars 37724.5 Emerging Markets 37724.6 Conclusions 37825 Review: The Critical Role of Clinical Pharmacology in the Development of Biologics 385Liang Zhao, Diane Wang, Ping Zhao, Elizabeth Y. Shang, Yaning Wang and Vikram Sinha25.1 Introduction 38525.2 PK and PD of Biologics 38525.3 Critical Role of Clinical Pharmacology and Related Regulatory Guidance for Biologics Development 38725.4 Model]Based Drug Development for Biologics 39325.5 Conclusions 39725.6 Disclaimer 39726 Investigating the Nonclinical ADME and PK/PD of an Antibody–Drug Conjugate: A Case Study of ADO]Trastuzumab Emtansine (T]DM1) 401Jay Tibbitts26.1 Introduction 40126.2 Importance of ADME for ADCs 40226.3 T]DM1 Bioanalytical Strategy and Methods 40326.4 Ex Vivo Linker Stability 40426.5 Plasma PK 40426.6 Distribution of T]DM1 40626.7 T]DM1 Catabolism and Elimination 40626.8 T]DM1 Nonclinical PK/PD 40826.9 Conclusions 40927 Use of PK/PD Knowledge in Guiding Bispecific Biologics Research and Development 413Andreas Baumann, Saileta Prabhu and Jitendra Kanodia27.1 Introduction 41327.2 Structural Formats and Generation of Bispecific Biologics 41527.3 Biochemistry and Pharmacology of Bispecifics 41627.4 Pharmacokinetics 41627.5 Pharmacokinetic–Pharmacodynamic Model]Informed Design of bsAbs 41827.6 Application of PK/PD in the Research and Development of Bispecific Biologics: Case Examples 41927.7 Outlook 421References 422Index 427

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).

"At the outset, one�s impressed with the scope of the book; it provides an outline of very diverse topics starting with the basics of protein engineering and how these are used to design and manipulate the ADME properties of recombinant and synthetic proteins...The authors have to be congratulated on their endeavor to stitch these topics together in a single book...With such a wide range of topics, even an experienced scientific practitioner in this area is likely to find something new to engage them and expand their knowledge...In summary, an excellent and comprehensive book for beginners to the CP/PK area to acquaint themselves with the area of biologics (specifically mAb) CP/PKPD principles and for experienced CP/PK scientists for reference." (CPT: Pharmacometrics & Systems Pharmacology, March 2017)

• List of Contributors xviiForeword xix1 ADME for Therapeutic Biologics: What Can We Leverage from Great Wealth of ADME Knowledge and Research for Small Molecules 1Weirong Wang and Thomayant Prueksaritanont1.1 Introduction 11.2 SM Drug Discovery and Development: Historical Perspective 11.3 LM Drug Discovery and Development 31.4 Conclusions 82 Protein Engineering: Applications to Therapeutic Proteins and Antibodies 13Andrew G. Popplewell2.1 Introduction 132.2 Methods of Protein Engineering 132.3 Applications of Protein Engineering to Non-Antibody Therapeutic Proteins 162.4 Applications of Protein Engineering to Therapeutic Antibodies 162.5 Future Perspectives 203 Therapeutic Antibodies—Protein Engineering to Influence ADME, PK, and Efficacy 25Tatsuhiko Tachibana, Kenta Haraya, Yuki Iwayanagi and Tomoyuki Igawa3.1 Introduction 253.2 Relationship between pI and Pharmacokinetics 263.3 Nonspecific/Specific Off]Target Binding 273.4 pH]Dependent Antigen Binding to Reduce Target]Mediated Elimination 283.5 Soluble Antigen Sweeping 313.6 Future Perspectives 344 ADME for Therapeutic Biologics: Antibody]Derived Proteins and Proteins with Novel Scaffolds 39Chetan Rathi and Bernd Meibohm4.1 Introduction 394.2 Antibody–Drug Conjugates 394.3 Bispecifics 454.4 Conclusions 505 Overview of ADME and PK/PD of ADCs 55Baiteng Zhao and Tae H. Han5.1 Introduction to ADC 555.2 Absorption 565.3 Distribution 585.4 Metabolism/Catabolism 585.5 Drug]Linker Stability 595.6 Elimination 605.7 Clinical PK 605.8 PK and PK/PD Modeling for ADCs 615.9 Summary 626 Role of Lymphatic System in Subcutaneous Absorption of Therapeutic Proteins 67Jiunn H. Lin and Weirong Wang6.1 Introduction 676.2 Physiology of Subcutaneous Tissue 686.3 Interstitial Transport from SC Injection Site 686.4 Relative Role of Blood and Lymphatic Systems in SC Absorption 696.5 Presystemic Catabolism in SC Absorption of Proteins 726.6 Effect of Injection Site on SC Absorption 746.7 Conclusions 747 Biodistribution of Therapeutic Biologics: Methods and Applications in Informing Target Biology, Pharmacokinetics, and Dosing Strategies 77Sean B. Joseph, Saileta Prabhu and C. Andrew Boswell7.1 Introduction 777.2 Determinants of Antibody Biodistribution 777.3 Methods of Measuring Antibody Biodistribution 817.4 Interpretation of Biodistribution Data 857.5 Concluding Remarks 878 Prediction of Human Pharmacokinetics for Protein]Based Biologic Therapeutics 91Chao Han and Christina Lourdes Mayer8.1 Introduction 918.2 General Allometric Scaling and Interspecies Scaling Methods 928.3 Considerations for Interspecies Scaling of Protein]Based Biologic Therapeutics 938.4 Physiologically Based PK Modeling 1008.5 Perspectives Beyond the Prediction 1018.6 Conclusions 1029 Fixed Dosing versus Body]Size]Based Dosing for Therapeutic Biologics—A Clinical Pharmacology Strategy 107Diane D. Wang, Justin T. Hoffman and Kourosh Parivar9.1 Introduction 1079.2 Conclusions 12210 Impact of Diseases, Comorbidity, and Target Physiology on ADME, PK, and PK/PD of Therapeutic Biologics 125Songmao Zheng, Weirong Wang and Honghui Zhou10.1 Introduction 12510.2 Impact of Diseases and Comorbidity on ADME and PK of Therapeutic Biologics 12610.3 Impact of Disease and Target Physiology on PK and PK/PD of Therapeutic Biologics 13010.4 Correlation between the PK of Therapeutic Biologics and Treatment Response 13410.5 Other Patient Characteristics that can Impact the Treatment Response of Therapeutic Biologics 13510.6 The Interplay between Disease, Target Physiology, and PK/PD of Therapeutic Biologics: Case Examples 13610.7 Concluding Remarks 13811 Immunogenicity: Its Impact on ADME of Therapeutic Biologics 147Harald Kropshofer and Wolfgang F. Richter11.1 Introduction 14711.2 Immunogenicity of Therapeutic Biologics 14711.3 Impact of ADA on ADME 15011.4 How to Deal with ADME Consequences of Immune Responses? 15511.5 Summary and Conclusions 15612 Mechanistic Physiologically Based Pharmacokinetic Models in Development of Therapeutic Monoclonal Antibodies 159Yanguang Cao and William J. Jusko12.1 Background 15912.2 History 15912.3 Principles and Methods       16212.4 Challenges 16512.5 Simplified PBPK Models for mAbs 16612.6 Perspectives 17113 Integrated Quantitation of Biotherapeutic Drug–Target Binding, Biomarkers, and Clinical Response to Support Rational Dose Regimen Selection 175Philip J. Lowe, Anne Kümmel, Christina Vasalou, Soichiro Matsushima and Andrej Skerjanec13.1 Introduction 17513.2 Methods 17613.3 Results and Discussion 18113.4 Conclusions 19114 Target]Driven Pharmacokinetics of Biotherapeutics 197Wilhelm Huisinga, Saskia Fuhrmann, Ludivine Fronton and Ben]Fillippo Krippendorff14.1 Introduction 19714.2 Soluble and Membrane]Bound Targets 19714.3 Whole]Body Target]Mediated Drug Disposition Models and Their Approximations 19814.4 Cell]Level Target]Mediated Drug Disposition Models 20314.5 Simplified Physiologically Based Pharmacokinetic Model for mAbs 20614.6 Conclusion: Looking at Data Through Models 20915 Target]Driven Pharmacokinetics of Biotherapeutics 213Guy M.L. Meno]Tetang15.1 Introduction 21315.2 Peptide–FC Fusion Proteins 21415.3 Monoclonal Antibodies (mAbs) 21515.4 Parameters Controlling Target]Driven Nonlinear Pharmacokinetics of Biotherapeutics 21815.5 Impact of Target]Driven Nonlinear Pharmacokinetics of Biotherapeutics on Halometric Scaling 22015.6 Conclusions and Perspectives 22016 Tumor Effect]Site Pharmacokinetics: Mechanisms and Impact on Efficacy 225Greg M. Thurber16.1 Introduction 22516.2 Tumor Pharmacokinetics 22516.3 Impact of Tumor Pharmacokinetics on Efficacy 23216.4 Conclusions 23517 Brain Effect Site Pharmacokinetics: Delivery of Biologics Across the Blood–Brain Barrier 241Gert Fricker and Anne Mahringer17.1 Cytotic Processes at the BBB 24317.2 Receptors at the BBB as Targets for Biologics 24317.3 "Trojan Horse" Approaches to Target BBB Receptors 24617.4 Colloidal Carriers for Drug Delivery 24817.5 Other Brain]Directed Carriers 24917.6 Stem Cell]Mediated Drug Delivery 25017.7 Focused Ultrasound and Microbubbles 25117.8 Conclusions and Perspectives 25118 Molecular Pathology Techniques in the Preclinical Development of Therapeutic Biologics 257Thierry Flandre, Sarah Taplin, Stewart Jones and Peter Lloyd18.1 Introduction 25718.2 Target Expression Profiling 25918.3 Off]Target Binding of the Therapeutic Biologic Reagent 26318.4 Biodistribution of Therapeutic Biologic Reagent 26418.5 Discussion 26518.6 Conclusion 26719 Labeling and Imaging Techniques for Quantification of Therapeutic Biologics 271Julie K. Jang, David Canter, Peisheng Hu, Alan L. Epstein and Leslie A. Khawli19.1 Introduction 27119.2 New and Conventional Methods for Labeling of Biologics 27219.3 Molecular Imaging for the Study of PK and Biodistribution of Biologics 28519.4 Conclusions and Perspectives 28820 Knowledge of ADME of Therapeutic Proteins in Adults Facilitates Pediatric Development 295Omoniyi J Adedokun and Zhenhua Xu20.1 Introduction 29520.2 Comparative Evaluation of ADME of Therapeutic Proteins between Adults and Children 29620.3 Extrapolation of Efficacy from Adults to Pediatric Patients 29820.4 Pediatric Dose Strategies 30020.5 Sample]Size Determination for Pediatric Studies 30420.6 Modeling and Simulation in Pediatric Drug Development Facilitated by Existing Adult Models 30520.6.1 Modeling and Simulation Framework for Therapeutic Proteins in Pediatric Drug Development 30520.6.2 Examples of the Application of Modeling and Simulation in the Development of Therapeutic Proteins in Pediatric Patients 30720.7 Future Directions 30921 LC/MS versus Immune]Based Bioanalytical Methods in Quantitation of Therapeutic Biologics in Biological Matrices 313Bo An, Ming Zhang and Jun Qu21.1 Introduction 31321.2 Comparison of the Characteristics in Method Development 31421.3 Comparison of Assay Performance 31621.4 Application of LBA and LC/MS in the Analysis of Therapeutic Proteins 32321.5 Summary and Future Perspective 32422 Biosimilar Development: Nonclinical and Clinical Strategies and Challenges with a Focus on the Role of PK/PD Assessments 331Susan Hurst and Donghua Yin22.1 Introduction 33122.2 Aspects of Biosimilarity 33222.3 Biosimilars’ Regulatory/Historical Perspective 33322.4 Nonclinical Assessments in the Development of Biosimilars 33622.5 Clinical PK and PD Assessments in the Development of Biosimilars 34022.6 Concluding Remarks 34423 ADME Processes in Vaccines and PK/PD Approaches for Vaccination Optimization 347José David Gómez]Mantilla, Iñaki F. Trocóniz and María J. Garrido23.1 Introduction 34723.2 Biopharmaceutic Considerations on Vaccine ADME Processes 35023.3 Vaccines and ADME Processes 35023.4 Mathematical Modeling for Vaccine Optimization in Cancer Treatment 36023.5 Systems Vaccinology: Application of Systems Biology in Personalized Vaccination 36223.6 Concluding Remarks 36324 Drug Development Strategies for Therapeutic Biologics: Industry Perspectives 369Theresa Yuraszeck and Megan Gibbs24.1 Introduction 36924.2 Preclinical Development 37224.3 Clinical Development 37524.4 Biosimilars 37724.5 Emerging Markets 37724.6 Conclusions 37825 Review: The Critical Role of Clinical Pharmacology in the Development of Biologics 385Liang Zhao, Diane Wang, Ping Zhao, Elizabeth Y. Shang, Yaning Wang and Vikram Sinha25.1 Introduction 38525.2 PK and PD of Biologics 38525.3 Critical Role of Clinical Pharmacology and Related Regulatory Guidance for Biologics Development 38725.4 Model]Based Drug Development for Biologics 39325.5 Conclusions 39725.6 Disclaimer 39726 Investigating the Nonclinical ADME and PK/PD of an Antibody–Drug Conjugate: A Case Study of ADO]Trastuzumab Emtansine (T]DM1) 401Jay Tibbitts26.1 Introduction 40126.2 Importance of ADME for ADCs 40226.3 T]DM1 Bioanalytical Strategy and Methods 40326.4 Ex Vivo Linker Stability 40426.5 Plasma PK 40426.6 Distribution of T]DM1 40626.7 T]DM1 Catabolism and Elimination 40626.8 T]DM1 Nonclinical PK/PD 40826.9 Conclusions 40927 Use of PK/PD Knowledge in Guiding Bispecific Biologics Research and Development 413Andreas Baumann, Saileta Prabhu and Jitendra Kanodia27.1 Introduction 41327.2 Structural Formats and Generation of Bispecific Biologics 41527.3 Biochemistry and Pharmacology of Bispecifics 41627.4 Pharmacokinetics 41627.5 Pharmacokinetic–Pharmacodynamic Model]Informed Design of bsAbs 41827.6 Application of PK/PD in the Research and Development of Bispecific Biologics: Case Examples 41927.7 Outlook 421References 422Index 427

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).

"At the outset, one�s impressed with the scope of the book; it provides an outline of very diverse topics starting with the basics of protein engineering and how these are used to design and manipulate the ADME properties of recombinant and synthetic proteins...The authors have to be congratulated on their endeavor to stitch these topics together in a single book...With such a wide range of topics, even an experienced scientific practitioner in this area is likely to find something new to engage them and expand their knowledge...In summary, an excellent and comprehensive book for beginners to the CP/PK area to acquaint themselves with the area of biologics (specifically mAb) CP/PKPD principles and for experienced CP/PK scientists for reference." (CPT: Pharmacometrics & Systems Pharmacology, March 2017)

• List of Contributors xviiForeword xix1 ADME for Therapeutic Biologics: What Can We Leverage from Great Wealth of ADME Knowledge and Research for Small Molecules 1Weirong Wang and Thomayant Prueksaritanont1.1 Introduction 11.2 SM Drug Discovery and Development: Historical Perspective 11.3 LM Drug Discovery and Development 31.4 Conclusions 82 Protein Engineering: Applications to Therapeutic Proteins and Antibodies 13Andrew G. Popplewell2.1 Introduction 132.2 Methods of Protein Engineering 132.3 Applications of Protein Engineering to Non-Antibody Therapeutic Proteins 162.4 Applications of Protein Engineering to Therapeutic Antibodies 162.5 Future Perspectives 203 Therapeutic Antibodies—Protein Engineering to Influence ADME, PK, and Efficacy 25Tatsuhiko Tachibana, Kenta Haraya, Yuki Iwayanagi and Tomoyuki Igawa3.1 Introduction 253.2 Relationship between pI and Pharmacokinetics 263.3 Nonspecific/Specific Off]Target Binding 273.4 pH]Dependent Antigen Binding to Reduce Target]Mediated Elimination 283.5 Soluble Antigen Sweeping 313.6 Future Perspectives 344 ADME for Therapeutic Biologics: Antibody]Derived Proteins and Proteins with Novel Scaffolds 39Chetan Rathi and Bernd Meibohm4.1 Introduction 394.2 Antibody–Drug Conjugates 394.3 Bispecifics 454.4 Conclusions 505 Overview of ADME and PK/PD of ADCs 55Baiteng Zhao and Tae H. Han5.1 Introduction to ADC 555.2 Absorption 565.3 Distribution 585.4 Metabolism/Catabolism 585.5 Drug]Linker Stability 595.6 Elimination 605.7 Clinical PK 605.8 PK and PK/PD Modeling for ADCs 615.9 Summary 626 Role of Lymphatic System in Subcutaneous Absorption of Therapeutic Proteins 67Jiunn H. Lin and Weirong Wang6.1 Introduction 676.2 Physiology of Subcutaneous Tissue 686.3 Interstitial Transport from SC Injection Site 686.4 Relative Role of Blood and Lymphatic Systems in SC Absorption 696.5 Presystemic Catabolism in SC Absorption of Proteins 726.6 Effect of Injection Site on SC Absorption 746.7 Conclusions 747 Biodistribution of Therapeutic Biologics: Methods and Applications in Informing Target Biology, Pharmacokinetics, and Dosing Strategies 77Sean B. Joseph, Saileta Prabhu and C. Andrew Boswell7.1 Introduction 777.2 Determinants of Antibody Biodistribution 777.3 Methods of Measuring Antibody Biodistribution 817.4 Interpretation of Biodistribution Data 857.5 Concluding Remarks 878 Prediction of Human Pharmacokinetics for Protein]Based Biologic Therapeutics 91Chao Han and Christina Lourdes Mayer8.1 Introduction 918.2 General Allometric Scaling and Interspecies Scaling Methods 928.3 Considerations for Interspecies Scaling of Protein]Based Biologic Therapeutics 938.4 Physiologically Based PK Modeling 1008.5 Perspectives Beyond the Prediction 1018.6 Conclusions 1029 Fixed Dosing versus Body]Size]Based Dosing for Therapeutic Biologics—A Clinical Pharmacology Strategy 107Diane D. Wang, Justin T. Hoffman and Kourosh Parivar9.1 Introduction 1079.2 Conclusions 12210 Impact of Diseases, Comorbidity, and Target Physiology on ADME, PK, and PK/PD of Therapeutic Biologics 125Songmao Zheng, Weirong Wang and Honghui Zhou10.1 Introduction 12510.2 Impact of Diseases and Comorbidity on ADME and PK of Therapeutic Biologics 12610.3 Impact of Disease and Target Physiology on PK and PK/PD of Therapeutic Biologics 13010.4 Correlation between the PK of Therapeutic Biologics and Treatment Response 13410.5 Other Patient Characteristics that can Impact the Treatment Response of Therapeutic Biologics 13510.6 The Interplay between Disease, Target Physiology, and PK/PD of Therapeutic Biologics: Case Examples 13610.7 Concluding Remarks 13811 Immunogenicity: Its Impact on ADME of Therapeutic Biologics 147Harald Kropshofer and Wolfgang F. Richter11.1 Introduction 14711.2 Immunogenicity of Therapeutic Biologics 14711.3 Impact of ADA on ADME 15011.4 How to Deal with ADME Consequences of Immune Responses? 15511.5 Summary and Conclusions 15612 Mechanistic Physiologically Based Pharmacokinetic Models in Development of Therapeutic Monoclonal Antibodies 159Yanguang Cao and William J. Jusko12.1 Background 15912.2 History 15912.3 Principles and Methods       16212.4 Challenges 16512.5 Simplified PBPK Models for mAbs 16612.6 Perspectives 17113 Integrated Quantitation of Biotherapeutic Drug–Target Binding, Biomarkers, and Clinical Response to Support Rational Dose Regimen Selection 175Philip J. Lowe, Anne Kümmel, Christina Vasalou, Soichiro Matsushima and Andrej Skerjanec13.1 Introduction 17513.2 Methods 17613.3 Results and Discussion 18113.4 Conclusions 19114 Target]Driven Pharmacokinetics of Biotherapeutics 197Wilhelm Huisinga, Saskia Fuhrmann, Ludivine Fronton and Ben]Fillippo Krippendorff14.1 Introduction 19714.2 Soluble and Membrane]Bound Targets 19714.3 Whole]Body Target]Mediated Drug Disposition Models and Their Approximations 19814.4 Cell]Level Target]Mediated Drug Disposition Models 20314.5 Simplified Physiologically Based Pharmacokinetic Model for mAbs 20614.6 Conclusion: Looking at Data Through Models 20915 Target]Driven Pharmacokinetics of Biotherapeutics 213Guy M.L. Meno]Tetang15.1 Introduction 21315.2 Peptide–FC Fusion Proteins 21415.3 Monoclonal Antibodies (mAbs) 21515.4 Parameters Controlling Target]Driven Nonlinear Pharmacokinetics of Biotherapeutics 21815.5 Impact of Target]Driven Nonlinear Pharmacokinetics of Biotherapeutics on Halometric Scaling 22015.6 Conclusions and Perspectives 22016 Tumor Effect]Site Pharmacokinetics: Mechanisms and Impact on Efficacy 225Greg M. Thurber16.1 Introduction 22516.2 Tumor Pharmacokinetics 22516.3 Impact of Tumor Pharmacokinetics on Efficacy 23216.4 Conclusions 23517 Brain Effect Site Pharmacokinetics: Delivery of Biologics Across the Blood–Brain Barrier 241Gert Fricker and Anne Mahringer17.1 Cytotic Processes at the BBB 24317.2 Receptors at the BBB as Targets for Biologics 24317.3 "Trojan Horse" Approaches to Target BBB Receptors 24617.4 Colloidal Carriers for Drug Delivery 24817.5 Other Brain]Directed Carriers 24917.6 Stem Cell]Mediated Drug Delivery 25017.7 Focused Ultrasound and Microbubbles 25117.8 Conclusions and Perspectives 25118 Molecular Pathology Techniques in the Preclinical Development of Therapeutic Biologics 257Thierry Flandre, Sarah Taplin, Stewart Jones and Peter Lloyd18.1 Introduction 25718.2 Target Expression Profiling 25918.3 Off]Target Binding of the Therapeutic Biologic Reagent 26318.4 Biodistribution of Therapeutic Biologic Reagent 26418.5 Discussion 26518.6 Conclusion 26719 Labeling and Imaging Techniques for Quantification of Therapeutic Biologics 271Julie K. Jang, David Canter, Peisheng Hu, Alan L. Epstein and Leslie A. Khawli19.1 Introduction 27119.2 New and Conventional Methods for Labeling of Biologics 27219.3 Molecular Imaging for the Study of PK and Biodistribution of Biologics 28519.4 Conclusions and Perspectives 28820 Knowledge of ADME of Therapeutic Proteins in Adults Facilitates Pediatric Development 295Omoniyi J Adedokun and Zhenhua Xu20.1 Introduction 29520.2 Comparative Evaluation of ADME of Therapeutic Proteins between Adults and Children 29620.3 Extrapolation of Efficacy from Adults to Pediatric Patients 29820.4 Pediatric Dose Strategies 30020.5 Sample]Size Determination for Pediatric Studies 30420.6 Modeling and Simulation in Pediatric Drug Development Facilitated by Existing Adult Models 30520.6.1 Modeling and Simulation Framework for Therapeutic Proteins in Pediatric Drug Development 30520.6.2 Examples of the Application of Modeling and Simulation in the Development of Therapeutic Proteins in Pediatric Patients 30720.7 Future Directions 30921 LC/MS versus Immune]Based Bioanalytical Methods in Quantitation of Therapeutic Biologics in Biological Matrices 313Bo An, Ming Zhang and Jun Qu21.1 Introduction 31321.2 Comparison of the Characteristics in Method Development 31421.3 Comparison of Assay Performance 31621.4 Application of LBA and LC/MS in the Analysis of Therapeutic Proteins 32321.5 Summary and Future Perspective 32422 Biosimilar Development: Nonclinical and Clinical Strategies and Challenges with a Focus on the Role of PK/PD Assessments 331Susan Hurst and Donghua Yin22.1 Introduction 33122.2 Aspects of Biosimilarity 33222.3 Biosimilars’ Regulatory/Historical Perspective 33322.4 Nonclinical Assessments in the Development of Biosimilars 33622.5 Clinical PK and PD Assessments in the Development of Biosimilars 34022.6 Concluding Remarks 34423 ADME Processes in Vaccines and PK/PD Approaches for Vaccination Optimization 347José David Gómez]Mantilla, Iñaki F. Trocóniz and María J. Garrido23.1 Introduction 34723.2 Biopharmaceutic Considerations on Vaccine ADME Processes 35023.3 Vaccines and ADME Processes 35023.4 Mathematical Modeling for Vaccine Optimization in Cancer Treatment 36023.5 Systems Vaccinology: Application of Systems Biology in Personalized Vaccination 36223.6 Concluding Remarks 36324 Drug Development Strategies for Therapeutic Biologics: Industry Perspectives 369Theresa Yuraszeck and Megan Gibbs24.1 Introduction 36924.2 Preclinical Development 37224.3 Clinical Development 37524.4 Biosimilars 37724.5 Emerging Markets 37724.6 Conclusions 37825 Review: The Critical Role of Clinical Pharmacology in the Development of Biologics 385Liang Zhao, Diane Wang, Ping Zhao, Elizabeth Y. Shang, Yaning Wang and Vikram Sinha25.1 Introduction 38525.2 PK and PD of Biologics 38525.3 Critical Role of Clinical Pharmacology and Related Regulatory Guidance for Biologics Development 38725.4 Model]Based Drug Development for Biologics 39325.5 Conclusions 39725.6 Disclaimer 39726 Investigating the Nonclinical ADME and PK/PD of an Antibody–Drug Conjugate: A Case Study of ADO]Trastuzumab Emtansine (T]DM1) 401Jay Tibbitts26.1 Introduction 40126.2 Importance of ADME for ADCs 40226.3 T]DM1 Bioanalytical Strategy and Methods 40326.4 Ex Vivo Linker Stability 40426.5 Plasma PK 40426.6 Distribution of T]DM1 40626.7 T]DM1 Catabolism and Elimination 40626.8 T]DM1 Nonclinical PK/PD 40826.9 Conclusions 40927 Use of PK/PD Knowledge in Guiding Bispecific Biologics Research and Development 413Andreas Baumann, Saileta Prabhu and Jitendra Kanodia27.1 Introduction 41327.2 Structural Formats and Generation of Bispecific Biologics 41527.3 Biochemistry and Pharmacology of Bispecifics 41627.4 Pharmacokinetics 41627.5 Pharmacokinetic–Pharmacodynamic Model]Informed Design of bsAbs 41827.6 Application of PK/PD in the Research and Development of Bispecific Biologics: Case Examples 41927.7 Outlook 421References 422Index 427