Quantitative Pharmacology and Individualized Therapy Strategies in Development of Therapeutic Proteins for Immune-Mediated Inflammatory Diseases

List of Contributors xvii About the Editors xxi Foreword xxiii Preface xxvii 1 Disease Interception in Autoimmune Diseases: From a Conceptual Framework to Practical Implementation 1 Anish Suri 1.1 Introduction to Disease Interception 1 1.2 Disease Interception in Autoimmune Diseases 3 1.3 Progress in Modulation of the Adaptive Immune Response in Autoimmune Inflammatory Diseases 5 1.4 The Complex Interplay between the Specificity of the Pathogenic Immune Repertoire and Its Sculpting by the Environment – Implications for Disease Interception 8 1.5 Clinical Application and Concluding Remarks 14 Acknowledgments 15 References 15 2 The Role of Biomarkers in Treatment Algorithms for Ulcerative Colitis (UC) 25 Reena Khanna and Brian G. Feagan 2.1 Background 25 2.2 Histology 32 2.2.1 Tissue Markers 33 2.3 Treatment Algorithms 34 2.3.1 Differentiating Inflammatory and Noninflammatory Disease 34 2.4 Assessing Response to Therapy 35 2.5 Predicting Relapse 35 2.6 Summary 35 References 35 3 Mechanism and Physiologically Based PK/PD Model in Assisting Translation from Preclinical to Clinical: Understanding PK/PD of Therapeutic Proteins at Site-of-Action 43 Xi Chen and Weirong Wang 3.1 Introduction 43 3.2 Biologic Distribution to Tissue Site of Action 44 3.3 Target Engagement of Biologics at Site of Action 50 3.4 Translational Application of Mechanistic PBPK Modeling 54 3.5 Conclusion 59 References 59 4 Application of Minimal Anticipated Biological Effect Level (MABEL) in Human Starting Dose Selection for Immunomodulatory Protein Therapeutics – Principles and Case Studies 65 Haiqing Wang, Zheng Yang, and Rong Shi 4.1 Introduction 65 4.2 Safety and Immune-Related Toxicities of Immunomodulatory Protein Therapeutics 66 4.3 Uncertainties of Toxicology Approach in FIH Safe Starting Dose Selection for Immunomodulatory Protein Therapeutics 68 4.4 Incorporating Mabel Approach in FIH Starting Dose Selection for High-Risk Immunomodulatory Protein Therapeutics 71 4.5 Case Studies of Mabel Calculation 75 4.6 Discussion and Conclusion 85 References 87 5 Model-Based Meta-Analysis Use in the Development of Therapeutic Proteins 93 Timothy J. Taylor, Bill Frame, and Angela D. Taylor 5.1 Introduction 93 5.2 Types of MBMA and Database Considerations 94 5.3 Data Analytic Models Useful for MBMA 96 5.4 Example 1: MBMA in Inflammatory Bowel Disease 97 5.5 MBMA Literature Search 99 5.6 Kinetic-Pharmacodynamic Models 100 5.7 MBMA Implications for Inflammatory Bowel Disease 116 5.8 Example 2: MBMA in Rheumatoid Arthritis 117 5.9 Conclusion 119 References 120 6 Utility of Joint Population Exposure–Response Modeling Approach to Assess Multiple Continuous and Categorical Endpoints in Immunology Drug Development 125 Chuanpu Hu and Honghui Zhou 6.1 Introduction 125 6.2 Latent Variable Indirect Response Models 126 6.3 Residual Correlation Modeling Between a Continuous and a Categorical Endpoint 128 6.4 Structural Correlation Modeling Between a Continuous Endpoint and a Categorical Endpoint 134 6.4.1 Application Example: Rheumatoid Arthritis 134 6.5 Conclusion 145 References 145 7 Modeling Approaches to Characterize Target-Mediated Pharmacokinetics and Pharmacodynamics for Therapeutic Proteins 149 Leonid Gibiansky and Ekaterina Gibiansky 7.1 Introduction 149 7.2 Target-Mediated Drug Disposition Model 150 7.3 Data and Practical Considerations 152 7.4 What to Expect from the Concentration–Time Course 154 7.5 Approximations of the TMDD Model 157 7.6 Identifiability of Model Parameters 166 7.7 Summary 167 References 168 8 Tutorial: Numerical (NONMEM) Implementation of the Target-Mediated Drug Disposition Model 173 Leonid Gibiansky and Ekaterina Gibiansky 8.1 Introduction 173 8.2 Notations and Data 174 8.3 NONMEM Code for TMDD Model and Approximations 174 8.4 How to Select Correct Approximation 179 8.4.2 Approach Based on Biological Considerations 180 8.5 Numerical Implementation 181 8.5.1 Choice of ADVAN Subroutines 181 8.5.2 Parallel Computing 181 8.6 Summary 182 References 182 9 Translational Considerations in Developing Bispecific Antibodies: What Can We Learn from Quantitative Pharmacology? 187 Pradeep B. Lukka, Santosh Wagh, and Bernd Meibohm 9.1 Introduction 187 9.2 Quantitative Pharmacokinetic Considerations of BsAbs 187 9.3 Preclinical Considerations 189 9.4 Translational Considerations 196 9.5 Immunogenicity 197 9.6 Clinical Development of BsAbs 198 9.7 Conclusion 200 References 202 10 Application of Pharmacometrics and Systems Pharmacology to Current and Emerging Biologics in Inflammatory Bowel Diseases 209 Sihem Ait-Oudhia, Yi Ting (Kayla) Lien, Sumit Basu, Lawrence Lesko, and Stephan Schmidt 10.1 Introduction 209 10.2 Pharmacological Approaches for the Treatment of IBD 215 10.3 Mathematical Models in IBD 224 10.4 Role of FDA in the Drug Development of Biologics in the Treatment of IBD 228 10.5 Summary 231 References 231 11 Pharmacokinetics-Based Dosing for Therapeutic Monoclonal Antibodies in Inflammatory Bowel Disease 243 Niels Vande Casteele and William J. Sandborn 11.1 Inflammatory Bowel Disease 243 11.2 Population Pharmacokinetics 244 11.3 Exposure–Response 246 11.4 Exposure-Based Dosing Strategies 247 11.5 Discussion 249 References 251 12 Pharmacokinetics-Based Dosing Strategies for Therapeutic Proteins in Inflammatory Bowel Disease 255 Diane R.Mould, Richard N. Upton, and Jessica Wojciechowski 12.1 Introduction 255 12.2 The Need for Understanding and Controlling Variability in Exposure 256 12.3 History of Dose Individualization 258 12.4 Bayesian Methods for Dose Individualization 260 12.5 Clinical Need for Improved Dosing with mAbs 265 12.6 Expectations for Bayesian Adaptive Dosing 268 12.7 Summary and Conclusions 277 References 278 13 Quantitative Pharmacology Approach to Select Optimal Dose and Study the Important Factors in Determining Disposition of Therapeutic Monoclonal Antibody in Pediatric Subjects – Some Considerations 285 Deni Hardiansyah and Chee M. Ng 13.1 Introduction 285 13.2 Pharmacokinetics of Therapeutic Monoclonal Antibody in Pediatric Population 289 13.3 Quantitative Pharmacology Considerations to Select Optimal Pediatric Dose of mAbs Based on Adult PK Studies 291 13.4 Using mPBPK Model to Study the Effects of FcRn Developmental Pharmacology on the PK of mAbs in Pediatric Subjects 299 References 307 14 Quantitative Pharmacology Assessment Strategy Therapeutic Proteins in Pediatric Subjects – Challenges and Opportunities 315 Jeremiah D. Momper, Andrew Mulberg, Nitin Mehrotra, Dan Turner, William Faubion, Laurie Conklin, Karim Azer, and Marla C. Dubinsky 14.1 Introduction 315 14.2 Extrapolation of Efficacy 315 14.3 Initiation of Pediatric Trials 321 14.4 Trial Design Considerations 322 14.5 Challenges in Pediatric Trials for First-in-Class vs. Follow-on Drug-in-Class 330 References 331 15 Case Examples of Using Quantitative Pharmacology in Developing Therapeutic Proteins for Plaque Psoriasis – Guselkumab 337 Zhenling Yao, Yaowei Zhu, Chuanpu Hu, Yang Chen, Shu Li, Bruce Randazzo, Zhenhua Xu, Amarnath Sharma, and Honghui Zhou 15.1 Introduction 337 15.1.1 Pathogenesis of Plaque Psoriasis 337 15.1.2 Current Treatment Paradigms for Psoriasis 338 15.2 Understanding of Exposure–Response (ER) Relationship of Guselkumab in Psoriasis 339 15.3 Dose Selection for Guselkumab in Psoriasis 342 15.4 Quantitative Pharmacology in Post-submission Support 358 15.5 Conclusion 359 References 360 16 Vedolizumab—A Case Example of Using Quantitative Pharmacology in Developing Therapeutic Biologics in Inflammatory Bowel Disease 363 Maria Rosario, Nathanael L. Dirks, Diane R.Mould, Catherine Scholz, Timothy Wyant, Asit Parikh, and Irving Fox Abbreviations 363 16.1 Introduction 364 16.2 Dose Selection for Adult Patients in Phase 3 Trials 365 16.3 Pharmacokinetic Profile of Vedolizumab 366 16.4 Population Pharmacokinetics in Phase 1 and 2 Trials 368 16.5 Comparison of Simulated vs. Measured Vedolizumab Trough Concentrations 372 16.6 Population Pharmacokinetics in Phase 3 Trials 372 16.7 Dose Selection for Pediatric Populations 374 16.8 Exposure–Response Analysis 376 16.9 Logistic Regression Analyses 378 16.10 Exposure–Response: Causal Inferences 381 16.11 Conclusion 384 Disclosure 384 References 384 17 Case Examples of Using Quantitative Pharmacology in Developing Therapeutic Proteins in Systemic Lupus Erythematosus – Belimumab 389 Herbert Struemper 17.1 Introduction 389 17.2 Overview of Supporting Data and Methods 390 17.3 Body Size Characterizations and Impact on Switching from Weight Proportional to Fixed Dosing 390 17.4 The Yin and Yang of FcRn – Opposing Effect of Albumin and IgG on mAb Clearance 392 17.5 Lost in Filtration – Renal Contributions to mAb Clearance 395 17.6 Conclusion 397 References 398 18 Case Examples of Using Quantitative Pharmacology in Developing Therapeutic Proteins in Multiple Sclerosis – Peginterferon Beta-1a, Daclizumab Beta, Natalizumab 401 Xiao Hu, Yaming Hang, Lei Diao, Kumar K.Muralidharan, and Ivan Nestorov 18.1 Introduction 401 18.2 Application of Quantitative Clinical Pharmacology for Dosing Regimen Recommendation of Peginterferon Beta- 1a 403 18.3 Population PK/PD Analyses of Daclizumab Beta and Phase 3 Dose Selection 414 18.4 Model-Based Approach for the Clinical Development of Subcutaneous Natalizumab 419 18.5 Summary 431 References 431 Index 437