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Applications in Drug Discovery and Development
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Main description:

Improve the discovery and development of protein drugs


Monoclonal antibodies, as the most successful class of protein therapeutics, have become a critical part of drug treatment regimens with more than 40 marketed modalities and hundreds under development. Some of them have become standards of care, in particular in areas such as oncology and immune–mediated inflammatory diseases; where they often provide safe and efficacious treatment alternatives. Nevertheless, limitations inherent in the canonical monospecific IgG–based monoclonal antibodies have prompted exploration of alternative molecular formats, such as antibody drug–conjugates (ADCs), bi– or multi–specific versions of antibodies. However, there is still scarcity of knowledge and data, combined with a lack of consistent strategies in effectively taking those candidate biologics from preclinical to clinical development. Recent years, though, have seen much progress in understanding ADME (absorption, distribution, metabolism and excretion) of biologics and how this knowledge can be used in research and development.

With an emphasis on the theoretical and practical aspects of ADME for therapeutic proteins, this book helps readers strategize, plan and implement end–to–end translational research. Understanding of ADME has clearly illustrated its merits in the area of small molecule drugs in order to develop drugs successfully and more effectively. Novel therapeutic modalities will even more require an in–depth understanding of ADME to optimize delivery for a successful development. The authors, writing from the frontlines of biologics research and development, cover topics that include similarities and differences in ADME characteristics between small molecules and biologics, the types of therapeutic biologics (e.g. monoclonal antibodies, pegylated proteins, vaccines, ADCs, and bispecifics) and their unique ADME properties, and how protein engineering alters and optimizes ADME and PK/PD properties.

A complete and valuable reference and resource for anyone working in the biopharmaceutical field, ADME and Translational Pharmacokinetics / Pharmacodynamics of Therapeutic Proteins offers features that include:

Concepts of ADME and PK/PD modeling for biologics
 Comparison of small molecules with biologics, giving a lessons–learned perspective
 Mechanistic insight in target–driven and local PK/PD in sites of action like tumors and the brain
 Case studies about leveraging ADME to improve end–to–end biologics drug development
 Current thinking and strategies on biosimilar development from ADME and PK/PD standpoints
 Regulatory expectations and industry perspectives for biologic development in USA, EU, and Japan


Back cover:

Improve the discovery and development of protein drugs


Monoclonal antibodies, as the most successful class of protein therapeutics, have become a critical part of drug treatment regimens with more than 40 marketed modalities and hundreds under development. Some of them have become standards of care, in particular in areas such as oncology and immune–mediated inflammatory diseases; where they often provide safe and efficacious treatment alternatives. Nevertheless, limitations inherent in the canonical monospecific IgG–based monoclonal antibodies have prompted exploration of alternative molecular formats, such as antibody drug–conjugates (ADCs), bi– or multi–specific versions of antibodies. However, there is still scarcity of knowledge and data, combined with a lack of consistent strategies in effectively taking those candidate biologics from preclinical to clinical development. Recent years, though, have seen much progress in understanding ADME (absorption, distribution, metabolism and excretion) of biologics and how this knowledge can be used in research and development.

With an emphasis on the theoretical and practical aspects of ADME for therapeutic proteins, this book helps readers strategize, plan and implement end–to–end translational research. Understanding of ADME has clearly illustrated its merits in the area of small molecule drugs in order to develop drugs successfully and more effectively. Novel therapeutic modalities will even more require an in–depth understanding of ADME to optimize delivery for a successful development. The authors, writing from the frontlines of biologics research and development, cover topics that include similarities and differences in ADME characteristics between small molecules and biologics, the types of therapeutic biologics (e.g. monoclonal antibodies, pegylated proteins, vaccines, ADCs, and bispecifics) and their unique ADME properties, and how protein engineering alters and optimizes ADME and PK/PD properties.

A complete and valuable reference and resource for anyone working in the biopharmaceutical field, ADME and Translational Pharmacokinetics / Pharmacodynamics of Therapeutic Proteins offers features that include:

Concepts of ADME and PK/PD modeling for biologics
 Comparison of small molecules with biologics, giving a lessons–learned perspective
 Mechanistic insight in target–driven and local PK/PD in sites of action like tumors and the brain
 Case studies about leveraging ADME to improve end–to–end biologics drug development
 Current thinking and strategies on biosimilar development from ADME and PK/PD standpoints
 Regulatory expectations and industry perspectives for biologic development in USA, EU, and Japan


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


1.2.1 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 Fc RIIb ]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 O ther 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 O malizumab, IgE, Itch, and Hives 176


13.2.2 QGE031 and Omalizumab, IgE, Basophil Fc R1 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 O malizumab Capture of IgE Reducing Itch and Hives 181


13.3.2 QGE031 and Omalizumab Capture of IgE, Reducing Basophil Fc R1, 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 O verview 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 O ther 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


PRODUCT DETAILS

ISBN-13: 9781118898802
Publisher: John Wiley & Sons Ltd (Wiley–Blackwell)
Publication date: January, 2016
Pages: 400
Dimensions: 150.00 x 284.00 x 31.16

Subcategories: Pharmacology

MEET THE AUTHOR

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).