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Book Description

Thorough Overview Identifies and Addresses Critical Gaps in the Treatment of Several Chronic Diseases 

With increasing numbers of patients suffering from Immune-Mediated Inflammatory Diseases (IMIDs), and with the increasing reliance on biopharmaceuticals to treat them, it is imperative that researchers and medical practitioners have a thorough understanding of the absorption, distribution, metabolism and excretion (ADME) of therapeutic proteins as well as translational pharmacokinetic/pharmacodynamic (PK/PD) modeling for them. This comprehensive volume answers that need to be addressed.

Featuring eighteen chapters from world-renowned experts and opinion leaders in pharmacology, translational medicine and immunology, editors Honghui Zhou and Diane Mould have curated a much-needed collection of research on the advanced applications of pharmacometrics and systems pharmacology to the development of biotherapeutics and individualized treatment strategies for the treatment of IMIDs. Authors discuss the pathophysiology of autoimmune diseases in addition to both theoretical and practical aspects of quantitative pharmacology for therapeutic proteins, current translational medicine research methodologies and novel thinking in treatment paradigm strategies for IMIDs. Other notable features include:

•          Contributions from well-known authors representing leading academic research centers, specialized contract research organizations and pharmaceutical industries whose pipelines include therapeutic proteins

•          Chapters on a wide range of topics (e.g., pathophysiology of autoimmune diseases, biomarkers in ulcerative colitis, model-based meta-analysis use in the development of therapeutic proteins)

•          Case studies of applying quantitative pharmacology approaches to guiding therapeutic protein drug development in IMIDs such as psoriasis, inflammatory bowel disease, multiple sclerosis and lupus

Zhou and Mould’s timely contribution to the critical study of biopharmaceuticals is a valuable resource for any academic and industry researcher working in pharmacokinetics, pharmacology, biochemistry, or biotechnology as well as the many clinicians seeking the safest and most effective treatments for patients dealing with chronic immune disorders.

Table of Contents

  1. Cover
  2. About the Editors
  3. Foreword
    1. References
  4. Preface
  5. 1 Disease Interception in Autoimmune Diseases: From a Conceptual Framework to Practical Implementation
    1. 1.1 Introduction to Disease Interception
    2. 1.2 Disease Interception in Autoimmune Diseases
    3. 1.3 Progress in Modulation of the Adaptive Immune Response in Autoimmune Inflammatory Diseases
    4. 1.4 The Complex Interplay between the Specificity of the Pathogenic Immune Repertoire and Its Sculpting by the Environment – Implications for Disease Interception
    5. 1.5 Clinical Application and Concluding Remarks
    6. Acknowledgments
    7. References
  6. 2 The Role of Biomarkers in Treatment Algorithms for Ulcerative Colitis (UC)
    1. 2.1 Background
    2. 2.2 Histology
    3. 2.3 Treatment Algorithms
    4. 2.4 Assessing Response to Therapy
    5. 2.5 Predicting Relapse
    6. 2.6 Summary
    7. References
  7. 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
    1. 3.1 Introduction
    2. 3.2 Biologic Distribution to Tissue Site of Action
    3. 3.3 Target Engagement of Biologics at Site of Action
    4. 3.4 Translational Application of Mechanistic PBPK Modeling
    5. 3.5 Conclusion
    6. References
  8. 4 Application of Minimal Anticipated Biological Effect Level (MABEL) in Human Starting Dose Selection for Immunomodulatory Protein Therapeutics – Principles and Case Studies
    1. 4.1 Introduction
    2. 4.2 Safety and Immune‐Related Toxicities of Immunomodulatory Protein Therapeutics
    3. 4.3 Uncertainties of Toxicology Approach in FIH Safe Starting Dose Selection for Immunomodulatory Protein Therapeutics
    4. 4.4 Incorporating Mabel Approach in FIH Starting Dose Selection for High‐Risk Immunomodulatory Protein Therapeutics
    5. 4.5 Case Studies of Mabel Calculation
    6. 4.6 Discussion and Conclusion
    7. References
  9. 5 5Model‐Based Meta‐Analysis Use in the Development of Therapeutic Proteins
    1. 5.1 Introduction
    2. 5.2 Types of MBMA and Database Considerations
    3. 5.3 Data Analytic Models Useful for MBMA
    4. 5.4 Example 1: MBMA in Inflammatory Bowel Disease
    5. 5.5 MBMA Literature Search
    6. 5.6 Kinetic‐Pharmacodynamic Models
    7. 5.7 MBMA Implications for Inflammatory Bowel Disease
    8. 5.8 Example 2: MBMA in Rheumatoid Arthritis
    9. 5.9 Conclusion
    10. References
  10. 6 Utility of Joint Population Exposure–Response Modeling Approach to Assess Multiple Continuous and Categorical Endpoints in Immunology Drug Development
    1. 6.1 Introduction
    2. 6.2 Latent Variable Indirect Response Models
    3. 6.3 Residual Correlation Modeling Between a Continuous and a Categorical Endpoint
    4. 6.4 Structural Correlation Modeling Between a Continuous Endpoint and a Categorical Endpoint
    5. 6.5 Conclusion
    6. References
  11. 7 Modeling Approaches to Characterize Target‐Mediated Pharmacokinetics and Pharmacodynamics for Therapeutic Proteins
    1. 7.1 Introduction
    2. 7.2 Target‐Mediated Drug Disposition Model
    3. 7.3 Data and Practical Considerations
    4. 7.4 What to Expect from the Concentration–Time Course
    5. 7.5 Approximations of the TMDD Model
    6. 7.6 Identifiability of Model Parameters
    7. 7.7 Summary
    8. References
  12. 8 Tutorial: Numerical (NONMEM) Implementation of the Target‐Mediated Drug Disposition Model
    1. 8.1 Introduction
    2. 8.2 Notations and Data
    3. 8.3 NONMEM Code for TMDD Model and Approximations
    4. 8.4 How to Select Correct Approximation
    5. 8.5 Numerical Implementation
    6. 8.6 Summary
    7. References
    8. Appendix Diagnostic Plots
  13. 9 Translational Considerations in Developing Bispecific Antibodies: What Can We Learn from Quantitative Pharmacology?
    1. 9.1 Introduction
    2. 9.2 Quantitative Pharmacokinetic Considerations of BsAbs
    3. 9.3 Preclinical Considerations
    4. 9.4 Translational Considerations
    5. 9.5 Immunogenicity
    6. 9.6 Clinical Development of BsAbs
    7. 9.7 Conclusion
    8. References
  14. 10 Application of Pharmacometrics and Systems Pharmacology to Current and Emerging Biologics in Inflammatory Bowel Diseases
    1. 10.1 Introduction
    2. 10.2 Pharmacological Approaches for the Treatment of IBD
    3. 10.3 Mathematical Models in IBD
    4. 10.4 Role of FDA in the Drug Development of Biologics in the Treatment of IBD
    5. 10.5 Summary
    6. References
  15. 11 Pharmacokinetics‐Based Dosing for Therapeutic Monoclonal Antibodies in Inflammatory Bowel Disease
    1. 11.1 Inflammatory Bowel Disease
    2. 11.2 Population Pharmacokinetics
    3. 11.3 Exposure–Response
    4. 11.4 Exposure‐Based Dosing Strategies
    5. 11.5 Discussion
    6. References
  16. 12 Pharmacokinetics‐Based Dosing Strategies for Therapeutic Proteins in Inflammatory Bowel Disease
    1. 12.1 Introduction
    2. 12.2 The Need for Understanding and Controlling Variability in Exposure
    3. 12.3 History of Dose Individualization
    4. 12.4 Bayesian Methods for Dose Individualization
    5. 12.5 Clinical Need for Improved Dosing with mAbs
    6. 12.6 Expectations for Bayesian Adaptive Dosing
    7. 12.7 Summary and Conclusions
    8. References
  17. 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
    1. 13.1 Introduction
    2. 13.2 Pharmacokinetics of Therapeutic Monoclonal Antibody in Pediatric Population
    3. 13.3 Quantitative Pharmacology Considerations to Select Optimal Pediatric Dose of mAbs Based on Adult PK Studies
    4. 13.4 Using mPBPK Model to Study the Effects of FcRn Developmental Pharmacology on the PK of mAbs in Pediatric Subjects
    5. References
  18. 14 Quantitative Pharmacology Assessment Strategy Therapeutic Proteins in Pediatric Subjects – Challenges and Opportunities
    1. 14.1 Introduction
    2. 14.2 Extrapolation of Efficacy
    3. 14.3 Initiation of Pediatric Trials
    4. 14.4 Trial Design Considerations
    5. 14.5 Challenges in Pediatric Trials for First‐in‐Class vs. Follow‐on Drug‐in‐Class
    6. References
  19. 15 Case Examples of Using Quantitative Pharmacology in Developing Therapeutic Proteins for Plaque Psoriasis – Guselkumab
    1. 15.1 Introduction
    2. 15.2 Understanding of Exposure–Response (ER) Relationship of Guselkumab in Psoriasis
    3. 15.3 Dose Selection for Guselkumab in Psoriasis
    4. 15.4 Quantitative Pharmacology in Post‐submission Support
    5. 15.5 Conclusion
    6. References
  20. 16 Vedolizumab—A Case Example of Using Quantitative Pharmacology in Developing Therapeutic Biologics in Inflammatory Bowel Disease
    1. Abbreviations
    2. 16.1 Introduction
    3. 16.2 Dose Selection for Adult Patients in Phase 3 Trials
    4. 16.3 Pharmacokinetic Profile of Vedolizumab
    5. 16.4 Population Pharmacokinetics in Phase 1 and 2 Trials
    6. 16.5 Comparison of Simulated vs. Measured Vedolizumab Trough Concentrations
    7. 16.6 Population Pharmacokinetics in Phase 3 Trials
    8. 16.7 Dose Selection for Pediatric Populations
    9. 16.8 Exposure–Response Analysis
    10. 16.9 Logistic Regression Analyses
    11. 16.10 Exposure–Response: Causal Inferences
    12. 16.11 Conclusion
    13. Disclosure
    14. References
  21. 17 Case Examples of Using Quantitative Pharmacology in Developing Therapeutic Proteins in Systemic Lupus Erythematosus – Belimumab
    1. 17.1 Introduction
    2. 17.2 Overview of Supporting Data and Methods
    3. 17.3 Body Size Characterizations and Impact on Switching from Weight Proportional to Fixed Dosing
    4. 17.4 The Yin and Yang of FcRn – Opposing Effect of Albumin and IgG on mAb Clearance
    5. 17.5 Lost in Filtration – Renal Contributions to mAb Clearance
    6. 17.6 Conclusion
    7. References
  22. 18 Case Examples of Using Quantitative Pharmacology in Developing Therapeutic Proteins in Multiple Sclerosis – Peginterferon Beta‐1a, Daclizumab Beta, Natalizumab
    1. 18.1 Introduction
    2. 18.2 Application of Quantitative Clinical Pharmacology for Dosing Regimen Recommendation of Peginterferon Beta‐ 1a
    3. 18.3 Population PK/PD Analyses of Daclizumab Beta and Phase 3 Dose Selection
    4. 18.4 Model‐Based Approach for the Clinical Development of Subcutaneous Natalizumab
    5. 18.5 Summary
    6. References
  23. Index
  24. End User License Agreement
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