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ADME and Translational Pharmacokinetics / Pharmacodynamics of Therapeutic Proteins

Applications in Drug Discovery and Development
1. Aufl.

von: Honghui Zhou, Frank-Peter Theil
134,99 €
Verlag:	Wiley
Format:	PDF
Veröffentl.:	26.10.2015
ISBN/EAN:	9781118898802
Sprache:	englisch
Anzahl Seiten:	480

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Beschreibungen

Titelbeschreibung

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

Inhaltsverzeichnis

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 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 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 O malizumab 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 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

Rezension

"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)

Autorenportrait

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).

Back cover copy

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