LIST OF CONTRIBUTORS xvii <p>FOREWORD xix</p> <p><b>1 ADME for Therapeutic Biologics: What Can We Leverage from Great Wealth of ADME Knowledge and <i>Research for Small Molecules 1</i></b><br /><i>Weirong Wang and Thomayant Prueksaritanont</i></p> <p>1.1 Introduction 1</p> <p>1.2 SM Drug Discovery and Development: Historical Perspective 1</p> <p>1.2.1 Evolving Role of DMPK: Paradigm Shift 1</p> <p>1.2.2 Key Enablers to Successful DMPK Support 2</p> <p>1.2.3 Regulatory Considerations 3</p> <p>1.3 LM Drug Discovery and Development 3</p> <p>1.3.1 Role of DMPK: Current State 3</p> <p>1.3.2 SM/LM DMPK Analogy 4</p> <p>1.3.3 Leveraging SM Experience: Case Examples 6</p> <p>1.4 Conclusions 8</p> <p>References 8</p> <p><b>2 Protein Engineering: Applications to Therapeutic Proteins and Antibodies 13</b><br /><i>Andrew G. Popplewell</i></p> <p>2.1 Introduction 13</p> <p>2.2 Methods of Protein Engineering 13</p> <p>2.2.1 General Techniques 13</p> <p>2.2.2 Introducing Specific, Directed Sequence Changes 14</p> <p>2.2.3 Fragment Fusion 14</p> <p>2.2.4 Gene Synthesis 14</p> <p>2.2.5 Molecular “Evolution” through Display and Selection 14</p> <p>2.3 Applications of Protein Engineering to Non-Antibody Therapeutic Proteins 16</p> <p>2.4 Applications of Protein Engineering to Therapeutic Antibodies 16</p> <p>2.4.1 Reduction of Immunogenicity 17</p> <p>2.4.2 Improving Stability and Biophysical Properties 17</p> <p>2.4.3 Tailoring Mechanism of Action 19</p> <p>2.4.4 Influencing Distribution and PK 19</p> <p>2.4.5 Improving Ligand/Receptor Interaction 20</p> <p>2.5 Future Perspectives 20</p> <p>References 21</p> <p><b>3 Therapeutic Antibodies—Protein Engineering to Influence ADME, PK, and Efficacy 25</b><br /><i>Tatsuhiko Tachibana, Kenta Haraya, Yuki Iwayanagi and Tomoyuki Igawa</i></p> <p>3.1 Introduction 25</p> <p>3.2 Relationship between pI and Pharmacokinetics 26</p> <p>3.2.1 pI and Clearance 26</p> <p>3.2.2 pI and Distribution 26</p> <p>3.2.3 pI and SC Absorption 27</p> <p>3.2.4 pI and FcRn Function 27</p> <p>3.3 Nonspecific/Specific Off?]Target Binding 27</p> <p>3.3.1 Nonspecific Binding and Clearance 27</p> <p>3.3.2 Specific Off?]Target Binding and Clearance 28</p> <p>3.4 pH?]Dependent Antigen Binding to Reduce Target?]Mediated Elimination 28</p> <p>3.4.1 Concept of Recycling Antibody 28</p> <p>3.4.2 pH Dependency and Target?]Mediated Elimination 29</p> <p>3.5 Soluble Antigen Sweeping 31</p> <p>3.5.1 Concept of Sweeping Antibody 31</p> <p>3.5.2 FcRn?]Mediated Sweeping 31</p> <p>3.5.3 FcγRIIb?]Mediated Sweeping 33</p> <p>3.6 Future Perspectives 34</p> <p>References 34</p> <p><b>4 ADME for Therapeutic Biologics: Antibody?]Derived Proteins and Proteins with Novel Scaffolds 39</b><br /><i>Chetan Rathi and Bernd Meibohm</i></p> <p>4.1 Introduction 39</p> <p>4.2 Antibody–Drug Conjugates 39</p> <p>4.2.1 Components of ADCs 40</p> <p>4.2.2 Types of ADC Analytes and Their PK Interpretation 41</p> <p>4.2.3 PK of ADC 42</p> <p>4.2.4 Immunogenicity of ADC 45</p> <p>4.2.5 Exposure–Response of ADCs 45</p> <p>4.2.6 Dose?]Dependent PK of ADCs 45</p> <p>4.3 Bispecifics 45</p> <p>4.3.1 Bispecific Antibody Formats 46</p> <p>4.3.2 PK of Bispecific Constructs 47</p> <p>4.3.3 Immunogenicity of Bispecific Constructs 48</p> <p>4.3.4 Examples of Bispecific Therapeutics—Oncology Indications 48</p> <p>4.3.5 Examples of Bispecific Therapeutics—CNS Indications 49</p> <p>4.3.6 Examples of Bispecific Therapeutics—Ocular Indications 49</p> <p>4.4 Conclusions 50</p> <p>References 50</p> <p><b>5 Overview of ADME and PK/PD of ADCs 55</b><br /><i>Baiteng Zhao and Tae H. Han</i></p> <p>5.1 Introduction to ADC 55</p> <p>5.2 Absorption 56</p> <p>5.3 Distribution 58</p> <p>5.4 Metabolism/Catabolism 58</p> <p>5.5 Drug?]Linker Stability 59</p> <p>5.6 Elimination 60</p> <p>5.7 Clinical PK 60</p> <p>5.8 PK and PK/PD Modeling for ADCs 61</p> <p>5.9 Summary 62</p> <p>References 63</p> <p><b>6 Role of Lymphatic System in Subcutaneous Absorption of Therapeutic Proteins 67</b><br /><i>Jiunn H. Lin and Weirong Wang</i></p> <p>6.1 Introduction 67</p> <p>6.2 Physiology of Subcutaneous Tissue 68</p> <p>6.3 Interstitial Transport from SC Injection Site 68</p> <p>6.4 Relative Role of Blood and Lymphatic Systems in SC Absorption 69</p> <p>6.5 Presystemic Catabolism in SC Absorption of Proteins 72</p> <p>6.6 Effect of Injection Site on SC Absorption 74</p> <p>6.7 Conclusions 74</p> <p>References 75</p> <p><b>7 Biodistribution of Therapeutic Biologics: Methods and Applications in Informing Target Biology, Pharmacokinetics, and Dosing Strategies 77</b><br /><i>Sean B. Joseph, Saileta Prabhu and C. Andrew Boswell</i></p> <p>7.1 Introduction 77</p> <p>7.2 Determinants of Antibody Biodistribution 77</p> <p>7.2.1 Molecular Properties 78</p> <p>7.2.2 Physiological (Tissue) Properties 79</p> <p>7.3 Methods of Measuring Antibody Biodistribution 81</p> <p>7.3.1 In Vivo Study Design Considerations 81</p> <p>7.3.2 Tissue Analysis 85</p> <p>7.4 Interpretation of Biodistribution Data 85</p> <p>7.4.1 Calculations and Units 86</p> <p>7.4.2 Compartmental Tissue Concentrations 86</p> <p>7.4.3 Blood Correction 86</p> <p>7.4.4 Derivation of Interstitial Concentrations 87</p> <p>7.4.5 Confirmation of Receptor Occupancy 87</p> <p>7.4.6 Explaining Unexpectedly Rapid Clearance 87</p> <p>7.4.7 Assisting in Clinical Dose Selection 87</p> <p>7.5 Concluding Remarks 87</p> <p>Acknowledgments 88</p> <p>References 88</p> <p><b>8 Prediction of Human Pharmacokinetics for Protein?]Based Biologic Therapeutics 91</b><br /><i>Chao Han and Christina Lourdes Mayer</i></p> <p>8.1 Introduction 91</p> <p>8.2 General Allometric Scaling and Interspecies Scaling Methods 92</p> <p>8.3 Considerations for Interspecies Scaling of Protein?]Based Biologic Therapeutics 93</p> <p>8.3.1 Considerations for Interspecies Scaling of mAbs 95</p> <p>8.3.2 Other Factors that may Affect PK Interspecies Scaling for Protein?]Based Therapeutics 98</p> <p>8.4 Physiologically Based PK Modeling 100</p> <p>8.5 Perspectives Beyond the Prediction 101</p> <p>8.5.1 Prediction of Human PK Serves Different Purposes at Different Stages of Drug Development 101</p> <p>8.5.2 Safety Considerations When Predicting Human PK for Protein?]Based Therapeutics 102</p> <p>8.6 Conclusions 102</p> <p>References 102</p> <p><b>9 Fixed Dosing versus Body?]Size?]Based Dosing for Therapeutic Biologics—A Clinical Pharmacology Strategy 107</b><br /><i>Diane D. Wang, Justin T. Hoffman and Kourosh Parivar</i></p> <p>9.1 Introduction 107</p> <p>9.1.1 Considerations for the Selection of a Dosing Approach 108</p> <p>9.1.2 Evaluations of Fixed Dosing versus Body?]Size?]Based Dosing 110</p> <p>9.1.3 Rationale Dosing Approach Selection Strategies Based on Stage of Clinical Development 121</p> <p>9.2 Conclusions 122</p> <p>References 122</p> <p><b>10 Impact of Diseases, Comorbidity, and Target Physiology on ADME, PK, and PK/PD of Therapeutic Biologics 125</b><br /><i>Songmao Zheng, Weirong Wang and Honghui Zhou</i></p> <p>10.1 Introduction 125</p> <p>10.1.1 ADME of Biologics 125</p> <p>10.1.2 Roles of TMDD for Biologics 126</p> <p>10.2 Impact of Diseases and Comorbidity on ADME and PK of Therapeutic Biologics 126</p> <p>10.2.1 Disease and Comorbidity on the Subcutaneous Absorption of Biologics 126</p> <p>10.2.2 Disease and Comorbidity on the Distribution of Biologics 127</p> <p>10.2.3 Hepatic Impairment 128</p> <p>10.2.4 Renal Impairment 128</p> <p>10.2.5 Immune?]Mediated Inflammatory Diseases 129</p> <p>10.2.6 Diabetes 129</p> <p>10.2.7 Immunogenicity 130</p> <p>10.3 Impact of Disease and Target Physiology on PK and PK/PD of Therapeutic Biologics 130</p> <p>10.3.1 Biologics against Membrane?]Bound Targets 130</p> <p>10.3.2 Biologics against Soluble Targets 133</p> <p>10.3.3 When Targets Exist as Both Membrane?]Bound and Soluble 133</p> <p>10.4 Correlation between the PK of Therapeutic Biologics and Treatment Response 134</p> <p>10.5 O ther Patient Characteristics that can Impact the Treatment Response of Therapeutic Biologics 135</p> <p>10.6 The Interplay between Disease, Target Physiology, and PK/PD of Therapeutic Biologics: Case Examples 136</p> <p>10.7 Concluding Remarks 138</p> <p>Acknowledgments 138</p> <p>References 138</p> <p><b>11 Immunogenicity: Its Impact on ADME of Therapeutic Biologics 147</b><br /><i>Harald Kropshofer and Wolfgang F. Richter</i></p> <p>11.1 Introduction 147</p> <p>11.2 Immunogenicity of Therapeutic Biologics 147</p> <p>11.2.1 The Underlying Cellular Immunology 147</p> <p>11.2.2 Aspects Facilitating Immune Responses against Biologics 149</p> <p>11.3 Impact of ADA on ADME 150</p> <p>11.3.1 Impact of ADA on Bioanalytical Results 150</p> <p>11.3.2 Formation of Immune Complexes 150</p> <p>11.3.3 Clearance of Immune Complexes 151</p> <p>11.3.4 Sustaining and Clearing ADAs 153</p> <p>11.3.5 Impact of ADAs on Distribution 155</p> <p>11.3.6 Impact of ADAs on Absorption 155</p> <p>11.4 How to Deal with ADME Consequences of Immune Responses? 155</p> <p>11.4.1 PK Assessment in the Presence of ADAs 155</p> <p>11.4.2 In?]Study Options to Overcome ADA Formation 156</p> <p>11.5 Summary and Conclusions 156</p> <p>References 157</p> <p><b>12 Mechanistic Physiologically Based Pharmacokinetic</b><br /><i>Models in Development of Therapeutic Monoclonal Antibodies 159</i></p> <p>Yanguang Cao and William J. Jusko</p> <p>12.1 Background 159</p> <p>12.2 History 159</p> <p>12.3 Principles and Methods 162</p> <p>12.4 Challenges 165</p> <p>12.4.1 Physiological Parameters 165</p> <p>12.4.2 Extravasation Mechanisms 165</p> <p>12.4.3 FcRn Function 165</p> <p>12.5 Simplified PBPK Models for mAbs 166</p> <p>12.5.1 Minimal PBPK Models 166</p> <p>12.5.2 Survey of mAb PK in Humans with the Minimal PBPK Model 168</p> <p>12.5.3 Minimal PBPK Model with Target?]Mediated Drug Disposition 169</p> <p>12.6 Perspectives 171</p> <p>Acknowledgments 172</p> <p>References 172</p> <p><b>13 Integrated Quantitation of Biotherapeutic Drug–Target Binding, Biomarkers, and Clinical Response to Support Rational Dose Regimen Selection 175</b><br /><i>Philip J. Lowe, Anne Kümmel, Christina Vasalou, Soichiro Matsushima and Andrej Skerjanec</i></p> <p>13.1 Introduction 175</p> <p>13.2 Methods 176</p> <p>13.2.1 O malizumab, IgE, Itch, and Hives 176</p> <p>13.2.2 QGE031 and Omalizumab, IgE, Basophil FcεR1 and Surface IgE, and Allergen Skin Prick Test Response 178</p> <p>13.2.3 Common Components 180</p> <p>13.3 Results and Discussion 181</p> <p>13.3.1 O malizumab Capture of IgE Reducing Itch and Hives 181</p> <p>13.3.2 QGE031 and Omalizumab Capture of IgE, Reducing Basophil FcεR1, Surface IgE, and Allergen Skin Reactivity 185</p> <p>13.4 Conclusions 191</p> <p>Acknowledgments 193</p> <p>References 193</p> <p><b>14 Target?]Driven Pharmacokinetics of Biotherapeutics 197</b><br /><i>Wilhelm Huisinga, Saskia Fuhrmann, Ludivine Fronton and Ben?]Fillippo Krippendorff</i></p> <p>14.1 Introduction 197</p> <p>14.2 Soluble and Membrane?]Bound Targets 197</p> <p>14.3 Whole?]Body Target?]Mediated Drug Disposition Models and Their Approximations 198</p> <p>14.3.1 Generic Whole?]Body TMDD Model 198</p> <p>14.3.2 Characteristics of Target?]Driven PK Profiles 199</p> <p>14.3.3 Location of the Target: Central versus Peripheral Compartment 200</p> <p>14.3.4 Parameter Identifiability and Model Reduction 200</p> <p>14.3.5 Extended Michaelis–Menten Approximation with Target Turnover 201</p> <p>14.3.6 Michaelis–Menten Approximation with Target Turnover 202</p> <p>14.3.7 Extended Michaelis–Menten Approximation 202</p> <p>14.3.8 Michaelis–Menten Approximation 203</p> <p>14.3.9 Model Selection 203</p> <p>14.4 Cell?]Level Target?]Mediated Drug Disposition Models 203</p> <p>14.4.1 Cell?]Level TMDD Model with a Single?]Cell Type 204</p> <p>14.4.2 Cell?]Level TMDD Model with Normal and Tumor Cells 204</p> <p>14.5 Simplified Physiologically Based Pharmacokinetic Model for mAbs 206</p> <p>14.5.1 Target?]Independent Pharmacokinetics 206</p> <p>14.5.2 Drug–Target Interaction 208</p> <p>14.6 Conclusion: Looking at Data Through Models 209</p> <p>Acknowledgment 209</p> <p>References 209</p> <p><b>15 Target?]Driven Pharmacokinetics of Biotherapeutics 213</b><br /><i>Guy M.L. Meno?]Tetang</i></p> <p>15.1 Introduction 213</p> <p>15.2 Peptide–FC Fusion Proteins 214</p> <p>15.3 Monoclonal Antibodies (mAbs) 215</p> <p>15.3.1 Antibodies Absorption 215</p> <p>15.3.2 Antibodies Distribution 215</p> <p>15.3.3 Mechanism of mAb Elimination 216</p> <p>15.3.4 Antibody–Drug Conjugates 217</p> <p>15.3.5 Recombinant Proteins 218</p> <p>15.4 Parameters Controlling Target?]Driven Nonlinear Pharmacokinetics of Biotherapeutics 218</p> <p>15.4.1 Target Localization 218</p> <p>15.4.2 Target Affinity 219</p> <p>15.4.3 Target Turnover 219</p> <p>15.4.4 Target Baseline and Disease Progression 219</p> <p>15.4.5 Off?]Target Binding 220</p> <p>15.5 Impact of Target?]Driven Nonlinear Pharmacokinetics of Biotherapeutics on Halometric Scaling 220</p> <p>15.5.1 Ethnic Differences 220</p> <p>15.6 Conclusions and Perspectives 220</p> <p>References 221</p> <p><b>16 Tumor Effect?]Site Pharmacokinetics: Mechanisms and Impact on Efficacy 225</b><br /><i>Greg M. Thurber</i></p> <p>16.1 Introduction 225</p> <p>16.2 Tumor Pharmacokinetics 225</p> <p>16.2.1 Tissue Physiology, Fluid Balance, and Macromolecular Transport 225</p> <p>16.2.2 Tumor Transport—An Overview 226</p> <p>16.2.3 Mechanisms of Tumor Transport 227</p> <p>16.2.4 Revisiting Tumor Transport Theory 229</p> <p>16.2.5 Impact of Drug Targeting Parameters on Distribution 231</p> <p>16.2.6 Experimental Validation and Comparison with Small Molecules 232</p> <p>16.3 Impact of Tumor Pharmacokinetics on Efficacy 232</p> <p>16.3.1 O verview of Cell?]Killing Mechanisms 232</p> <p>16.3.2 Pharmacokinetic Impact on Efficacy 233</p> <p>16.4 Conclusions 235</p> <p>References 236</p> <p><b>17 Brain Effect Site Pharmacokinetics: Delivery of Biologics Across the Blood–Brain Barrier 241</b><br /><i>Gert Fricker and Anne Mahringer</i></p> <p>17.1 Cytotic Processes at the BBB 243</p> <p>17.2 Receptors at the BBB as Targets for Biologics 243</p> <p>17.2.1 Transferrin Receptor 243</p> <p>17.2.2 Insulin Receptor 244</p> <p>17.2.3 Insulin?]Like Growth Factor Receptor 244</p> <p>17.2.4 LDL Receptor 244</p> <p>17.2.5 Low Density Lipoprotein Receptor?]Related Protein 1 245</p> <p>17.2.6 Low Density Lipoprotein Receptor?]Related Protein 2 245</p> <p>17.2.7 Leptin Receptor (OBR) 245</p> <p>17.2.8 Receptor of Advanced Glycation Endproducts 245</p> <p>17.2.9 Scavenger Receptor(SR) 246</p> <p>17.3 “Trojan Horse” Approaches to Target BBB Receptors 246</p> <p>17.4 Colloidal Carriers for Drug Delivery 248</p> <p>17.5 O ther Brain?]Directed Carriers 249</p> <p>17.6 Stem Cell?]Mediated Drug Delivery 250</p> <p>17.7 Focused Ultrasound and Microbubbles 251</p> <p>17.8 Conclusions and Perspectives 251</p> <p>References 251</p> <p><b>18 Molecular Pathology Techniques in the Preclinical Development of Therapeutic Biologics 257</b><br /><i>Thierry Flandre, Sarah Taplin, Stewart Jones and Peter Lloyd</i></p> <p>18.1 Introduction 257</p> <p>18.2 Target Expression Profiling 259</p> <p>18.2.1 Detection of DNA/RNA?]Based Target Expression Using Whole Tissue Extracts 259</p> <p>18.2.2 Detection of Protein?]Based Target Expression Using Whole Tissue Extracts 260</p> <p>18.2.3 Localization of DNA/RNA and Protein?]Based Target Expression at the Cellular Level Using Tissue Sections 262</p> <p>18.3 Off?]Target Binding of the Therapeutic Biologic Reagent 263</p> <p>18.3.1 Tissue Cross?]Reactivity Study 263</p> <p>18.3.2 Protein Microarray 264</p> <p>18.3.3 Cell Microarray Technology (Retrogenix) 264</p> <p>18.3.4 Protein Pull?]Down Assays 264</p> <p>18.4 Biodistribution of Therapeutic Biologic Reagent 264</p> <p>18.4.1 Whole?]Body Autoradiography 264</p> <p>18.4.2 Biodistribution: Immunohistochemistry Methods for Protein?]Based Therapeutic Products 265</p> <p>18.4.3 Biodistribution: Quantitative PCR Methods DNA/RNA?]Based Therapeutic Products 265</p> <p>18.5 Discussion 265</p> <p>18.5.1 Considerations in the Interpretation of Molecular Pathology?]Based Data 265</p> <p>18.5.2 Examples of Molecular Pathology Methods Used in Preclinical Development 266</p> <p>18.6 Conclusion 267</p> <p>References 267</p> <p><b>19 Labeling and Imaging Techniques for Quantification of Therapeutic Biologics 271</b><br /><i>Julie K. Jang, David Canter, Peisheng Hu, Alan L. Epstein and Leslie A. Khawli</i></p> <p>19.1 Introduction 271</p> <p>19.2 New and Conventional Methods for Labeling of Biologics 272</p> <p>19.2.1 Choice of Labels 272</p> <p>19.2.2 Labeling Strategies of Biologics 277</p> <p>19.3 Molecular Imaging for the Study of PK and Biodistribution of Biologics 285</p> <p>19.3.1 SPECT Imaging 286</p> <p>19.3.2 PET Imaging 286</p> <p>19.3.3 Optical Imaging 288</p> <p>19.4 Conclusions and Perspectives 288</p> <p>References 289</p> <p><b>20 Knowledge of ADME of Therapeutic Proteins in Adults Facilitates Pediatric Development 295</b><br /><i>Omoniyi J Adedokun and Zhenhua Xu</i></p> <p>20.1 Introduction 295</p> <p>20.2 Comparative Evaluation of ADME of Therapeutic Proteins between Adults and Children 296</p> <p>20.2.1 Absorption 296</p> <p>20.2.2 Distribution 297</p> <p>20.2.3 Metabolism and Elimination 297</p> <p>20.3 Extrapolation of Efficacy from Adults to Pediatric Patients 298</p> <p>20.3.1 No Extrapolation Approach 298</p> <p>20.3.2 Partial Extrapolation Approach 298</p> <p>20.3.3 Full Extrapolation Approach 299</p> <p>20.4 Pediatric Dose Strategies 300</p> <p>20.4.1 Body Weight?]Based (Linear) Dose?]Adjustment Approach 300</p> <p>20.4.2 BSA?]Based (Linear) Dose?]Adjustment Approach 304</p> <p>20.4.3 Tiered?]Fixed Dose?]Adjustment Approach 304</p> <p>20.4.4 Hybrid Dose?]Adjustment Approach 304</p> <p>20.4.5 Other Dose?]Adjustment Approaches 304</p> <p>20.5 Sample?]Size Determination for Pediatric Studies 304</p> <p>20.6 Modeling and Simulation in Pediatric Drug Development Facilitated by Existing Adult Models 305</p> <p>20.6.1 Modeling and Simulation Framework for Therapeutic Proteins in Pediatric Drug Development 305</p> <p>20.6.2 Examples of the Application of Modeling and Simulation in the Development of Therapeutic Proteins in Pediatric Patients 307</p> <p>20.7 Future Directions 309</p> <p>References 309</p> <p><b>21 LC/MS versus Immune?]Based Bioanalytical Methods in Quantitation of Therapeutic Biologics in Biological Matrices 313</b><br /><i>Bo An, Ming Zhang and Jun Qu</i></p> <p>21.1 Introduction 313</p> <p>21.2 Comparison of the Characteristics in Method Development 314</p> <p>21.2.1 Method Development Time 314</p> <p>21.2.2 Specificity 314</p> <p>21.2.3 Characteristics of Method Development 314</p> <p>21.3 Comparison of Assay Performance 316</p> <p>21.3.1 Sample Preparation 316</p> <p>21.3.2 Calibration Curve and Linearity Range 318</p> <p>21.3.3 Applicability 318</p> <p>21.3.4 Accuracy 319</p> <p>21.3.5 Sensitivity 319</p> <p>21.3.6 Reproducibility 321</p> <p>21.4 Application of LBA and LC/MS in the Analysis of Therapeutic Proteins 323</p> <p>21.4.1 Quantification of mAb in Plasma and Tissues 323</p> <p>21.4.2 Application in Multiplexed Analysis 323</p> <p>21.4.3 Characterization of Antibody–Drug Conjugates (ADC) 324</p> <p>21.5 Summary and Future Perspective 324</p> <p>References 324</p> <p><b>22 Biosimilar Development: Nonclinical and Clinical Strategies and Challenges with a Focus on the Role of PK/PD Assessments 331</b><br /><i>Susan Hurst and Donghua Yin</i></p> <p>22.1 Introduction 331</p> <p>22.2 Aspects of Biosimilarity 332</p> <p>22.3 Biosimilars’ Regulatory/Historical Perspective 333</p> <p>22.3.1 European Union 333</p> <p>22.3.2 EMA Nonclinical In Vivo Considerations 333</p> <p>22.3.3 EMA Clinical Considerations (Related to PK/PD) 334</p> <p>22.3.4 United States 334</p> <p>22.3.5 FDA Nonclinical In Vivo Considerations 335</p> <p>22.3.6 FDA Clinical Considerations (Related to PK/PD) 335</p> <p>22.3.7 The WHO and Other Global Markets 336</p> <p>22.4 Nonclinical Assessments in the Development of Biosimilars 336</p> <p>22.4.1 Biosimilars Nonclinical Development 336</p> <p>22.4.2 Designing the Nonclinical In Vivo Study 336</p> <p>22.4.3 Designing the Nonclinical Study: Immunogenicity/Bioanalytical 337</p> <p>22.4.4 Designing the Nonclinical In Vivo Study—PK and PD Focus 337</p> <p>22.4.5 Designing the Nonclinical In Vivo Study—No Relevant Nonclinical Species 338</p> <p>22.5 Clinical PK and PD Assessments in the Development of Biosimilars 340</p> <p>22.5.1 Biosimilars Clinical Development 340</p> <p>22.5.2 Bioanalytical Assays for Biosimilars PK and PD Investigations 341</p> <p>22.5.3 Design Considerations for Phase I PK and PD Similarity Studies 341</p> <p>22.5.4 PK Similarity Study of PF?]05280014, a Proposed Biosimilar to Trastuzumab: An Example 342</p> <p>22.5.5 Extrapolation of Clinical Data 342</p> <p>22.6 Concluding Remarks 344</p> <p>Acknowledgments 344</p> <p>References 344</p> <p><b>23 ADME Processes in Vaccines and PK/PD Approaches for Vaccination Optimization 347</b><br /><i>José David Gómez?]Mantilla, Iñaki F. Trocóniz and María J. Garrido</i></p> <p>23.1 Introduction 347</p> <p>23.1.1 Vaccine Development 347</p> <p>23.1.2 Types of Vaccines 348</p> <p>23.1.3 Basic Immunological Mechanism of Vaccine Development 348</p> <p>23.2 Biopharmaceutic Considerations on Vaccine ADME Processes 350</p> <p>23.3 Vaccines and ADME Processes 350</p> <p>23.3.1 Effect of Vaccine Formulation on ADME 351</p> <p>23.3.2 Effect of Route of Administration 353</p> <p>23.3.3 Metabolism and Excretion 357</p> <p>23.3.4 PK Considerations 357</p> <p>23.4 Mathematical Modeling for Vaccine Optimization in Cancer Treatment 360</p> <p>23.5 Systems Vaccinology: Application of Systems Biology in Personalized Vaccination 362</p> <p>23.6 Concluding Remarks 363</p> <p>References 363</p> <p><b>24 Drug Development Strategies for Therapeutic Biologics: Industry Perspectives 369</b><br /><i>Theresa Yuraszeck and Megan Gibbs</i></p> <p>24.1 Introduction 369</p> <p>24.1.1 Biologics Properties and Classification 370</p> <p>24.1.2 Assay Development and Validation 372</p> <p>24.2 Preclinical Development 372</p> <p>24.2.1 FIH Starting Dose 374</p> <p>24.3 Clinical Development 375</p> <p>24.3.1 Intrinsic and Extrinsic Factors 375</p> <p>24.3.2 Special Populations: Renal and Hepatic Impairment 376</p> <p>24.3.3 Special Populations: Pediatrics 376</p> <p>24.4 Biosimilars 377</p> <p>24.5 Emerging Markets 377</p> <p>24.6 Conclusions 378</p> <p>References 379</p> <p><b>25 Review: The Critical Role of Clinical Pharmacology in the Development of Biologics 385</b><br /><i>Liang Zhao, Diane Wang, Ping Zhao, Elizabeth Y. Shang, Yaning Wang and Vikram Sinha</i></p> <p>25.1 Introduction 385</p> <p>25.2 PK and PD of Biologics 385</p> <p>25.2.1 Structural Difference between SMDs and Biological Products 385</p> <p>25.2.2 Route of Administration and Absorption 386</p> <p>25.2.3 Distribution 386</p> <p>25.2.4 Metabolism and Elimination 386</p> <p>25.2.5 mAb Distribution 386</p> <p>25.2.6 Catabolism and Elimination 387</p> <p>25.2.7 Other Biologics 387</p> <p>25.3 Critical Role of Clinical Pharmacology and Related Regulatory Guidance for Biologics Development 387</p> <p>25.3.1 First?]in?]Human (FIH) Dose Determination and Study Design 387</p> <p>25.3.2 Critical Considerations from a Standpoint of Clinical Pharmacology in Biologics Development 388</p> <p>25.4 Model?]Based Drug Development for Biologics 393</p> <p>25.4.1 Fixed Dosing versus Body Size?]Adjusted Dosing 394</p> <p>25.4.2 Mechanism?] and Physiologically Based Models for mAbs 394</p> <p>25.4.3 Utility of Meta?]Analysis 395</p> <p>25.4.4 Utility of Case–Control Analysis in Biologics Development 396</p> <p>25.5 Conclusions 397</p> <p>25.6 Disclaimer 397</p> <p>References 397</p> <p><b>26 Investigating the Nonclinical ADME and PK/PD of an Antibody–Drug Conjugate: A Case Study of ADO?]Trastuzumab Emtansine (T?]DM1) 401</b><br /><i>Jay Tibbitts</i></p> <p>26.1 Introduction 401</p> <p>26.2 Importance of ADME for ADCs 402</p> <p>26.3 T?]DM1 Bioanalytical Strategy and Methods 403</p> <p>26.4 Ex Vivo Linker Stability 404</p> <p>26.5 Plasma PK 404</p> <p>26.6 Distribution of T?]DM1 406</p> <p>26.7 T?]DM1 Catabolism and Elimination 406</p> <p>26.8 T?]DM1 Nonclinical PK/PD 408</p> <p>26.9 Conclusions 409</p> <p>References 409</p> <p><b>27 Use of PK/PD Knowledge in Guiding Bispecific Biologics Research and Development 413</b><br /><i>Andreas Baumann, Saileta Prabhu and Jitendra Kanodia</i></p> <p>27.1 Introduction 413</p> <p>27.2 Structural Formats and Generation of Bispecific Biologics 415</p> <p>27.3 Biochemistry and Pharmacology of Bispecifics 416</p> <p>27.3.1 Affinity 416</p> <p>27.3.2 Avidity 416</p> <p>27.4 Pharmacokinetics 416</p> <p>27.4.1 PK Assay Strategies Employed for the Development of bsAbs 417</p> <p>27.4.2 Immunogenicity Strategies Employed for the Development of bsAbs 418</p> <p>27.5 Pharmacokinetic–Pharmacodynamic Model?]Informed Design of bsAbs 418</p> <p>27.6 Application of PK/PD in the Research and Development of Bispecific Biologics: Case Examples 419</p> <p>27.6.1 Anti?]TfR/BACE1 to Improve Therapeutic Antibody Transport across the Blood–Brain Barrier 419</p> <p>27.6.2 PK Characterization to Optimize bsAb Molecule Design and Selection for Ophthalmology 420</p> <p>27.6.3 Pharmacokinetic Studies during Development of a Bispecific T?]Cell Engager 421</p> <p>27.7 Outlook 421</p> <p>References 422</p> <p>Index 427</p>