HONGHUI ZHOU, PHD, FCP, FAAPS, is a Senior Director and Janssen Fellow as well as US Head of Pharmacometrics at Janssen Research & Development, LLC.

DIANE R. MOULD, PHD, FCP, FAAPS, is President of Projections Research Inc., a consulting company offering pharmacokinetic and pharmacometric services, and the founder of Baysient LLC, a company that develops systems to individualize doses of drugs that are difficult to manage.

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

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