Sihem Ait‐Oudhia

University of Florida

Orlando, FL, USA

Karim Azer

Bill & Melinda Gates Medical Research Institute

Boston, MA, USA

Sumit Basu

University of Florida

Orlando, FL, USA

Niels Vande Casteele

University of California, San Diego

La Jolla, CA, USA

Yang Chen

Janssen Research & Development, LLC

Spring House, PA, USA

Xi (Cindy) Chen

Bristol‐Myers Squibb

Princeton, NJ, USA

Laurie Conklin

Children's Hospital

Washington, DC, USA

Lei Diao

BMS China

Shanghai, China

Nathanael L. Dirks

Metrum Research Group

Tariffville, CT, USA

Marla Dubinsky

Icahn School of Medicine at Mount Sinai

New York, NY, USA

William Faubion

Mayo Clinic

Rochester, MN, USA

Brian G. Feagan

University of Western Ontario

London, Ontario, Canada

Irving Fox

Takeda Pharmaceuticals

Cambridge, MA, USA

Bill Frame

Projections Research Inc.

CT, USA

Ekaterina Gibiansky

QuantPharm LLC

North Potomac, MD, USA

Leonid Gibiansky

QuantPharm LLC

North Potomac, MD, USA

Deni Hardiansyah

University of Kentucky

Lexington,

KY, USA

Chuanpu Hu

Janssen Research and Development

LLC,

Spring House, PA, USA

Xiao Hu

Wave Life Sciences

Cambridge,

MA, USA

Kumar Kandadi Muralidharan

Biogen Idec

Cambridge, MA, USA

Reena Khanna

University of Western Ontario

London, Ontario, Canada

Yi Ting (Kayla) Lien

University of Florida

Orlando, FL, USA

Lawrence Lesko

University of Florida

Orlando, FL, USA

Shu Li

Janssen Research & Development, LLC

Spring House, PA, USA

Pradeep B. Lukka

The University of Tennessee Health Science Center

Memphis, TN, USA

Bernd Meibohm

The University of Tennessee Health Science Center

Memphis, TN, USA

Diane R. Mould

Projections Research Inc.

Phoenixville, PA, USA

Jeremiah D. Momper

University of California, San Diego

La Jolla, San Diego, CA, USA

Andrew Mulberg

Amicus Therapeutics, Inc.

Cranbury, NJ, USA

Nitin Mehrotra

Merck & Co.

North Wales, PA, USA

Chee Ng

University of Kentucky

Lexington,

KY, USA

Ivan Nestorov

Biogen Idec

Cambridge, MA, USA

Asit Parikh

Curis, Inc.

Lexington, MA, USA

Bruce Randazzo

Janssen Research & Development, LLC

Spring House, PA, USA

Maria Rosario

Takeda Development Center Americas, Inc.

Cambridge, MA, USA

Amarnath Sharma

Janssen Research & Development, LLC

Spring House, PA, USA

Catherine Scholz

Kura Oncology

Cambridge, MA, USA

Herbert Struemper

GSK

Research Triangle Park, NC, USA

Stephan Schmidt

University of Florida

Orlando, FL, USA

William Sandborn

University of California, San Diego

La Jolla, CA, USA

Rong Shi

Bristol‐Myers Squibb

Lawrenceville, NJ, USA

Anish Suri

Cue Biopharma

Cambridge, MA, USA

Dan Turner

The Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition Shaare Zedek Medical Center

Jerusalem, Israel

Tim Taylor

Projections Research, Inc.

Phoenixville, PA, USA

Angela D. Taylor

Projections Research Inc.

Phoenixville, PA, USA

Richard N. Upton

University of South Australia

Adelaide, SA, Australia

Santosh Wagh

The University of Tennessee Health Science Center

Memphis, TN, USA

Jessica Wojciechowski

Pfizer Inc.

Groton, CT, USA

Weirong Wang

Janssen R&D, LLC

Spring House, PA, USA

Haiqing Wang

Bristol‐Myers Squibb Co.

Lawrenceville, NJ, USA

Timothy Wyant

Projections Research Inc.

Phoenixville, PA, USA

Zhenhua Xu

Janssen Research & Development, LLC

Spring House, PA, USA

Zhenling Yao

Janssen Research & Development, LLC

Spring House, PA, USA

Zheng Yang

Bristol‐Myers Squibb Co.

Lawrenceville, NJ, USA

Honghui Zhou

Janssen Research and Development, LLC

Spring House, PA, USA

Yaowei Zhu

Janssen Research & Development, LLC

Spring House, PA, USA

Honghui Zhou, PhD, FCP, FAAPS is currently Senior Director and Janssen Fellow, at Janssen Research & Development and US Head of Pharmacometrics in Clinical Pharmacology and Pharmacometrics. Before that, Dr. Zhou took different roles including Immunology Therapeutic Area Head in Global Clinical Pharmacology, US Head of Pharmacometrics in Model‐Based Drug Development, and Head of Biologics Pharmacokinetics and Pharmacodynamcis at the same company. Prior to joining Janssen, he was a Director of Clinical Pharmacology at Wyeth Research. He also worked for Novartis Pharmaceuticals Corp. and Johnson & Johnson Pharmaceutical Research & Development in the area of clinical pharmacology in both small molecular drugs and therapeutic proteins.

Dr. Zhou has authored and coauthored more than 200 original peer‐reviewed scientific papers, book chapters, and conference abstracts in PK/PD, drug–drug interactions, and therapeutic biologics drug development. In 2013, he coedited a book entitled, Drug–Drug Interactions for Therapeutic Biologics (Wiley), and in 2015, he coedited a book entitled ADME and Translational Pharmacokinetics/Pharmacodynamics of Therapeutic Proteins (Wiley). He has been an invited speaker in many national and international conferences. Dr. Zhou is board certified by American Board of Clinical Pharmacology (ABCP) and was elected Fellow of Clinical Pharmacology (FCP) of American College of Clinical Pharmacology (ACCP) in 1999 and Fellow of American Association of Pharmaceutical Scientists (AAPS) in 2013. He served as Section Editor for Biologics for the Journal of Clinical Pharmacology (2006–2013) and currently serves in its Editorial Board. He also serves as an Assistant Editor for mAbs. Dr. Zhou served in Board of Regents of ACCP from 2009–2013 and is currently serving another term from 2016–2020. He is a graduate of the China Pharmaceutical University, Bachelor degree in Pharmacology, and the University of Iowa, PhD in Pharmaceutics.

Diane R. Mould, PhD, FCP, FAAPS has spent 29 years as a pharmacokineticist in industry where she specialized in population pharmacokinetic/pharmacodynamic modeling and was an associate Research Professor at Georgetown University. She has conducted population PK/PD analyses of hematopoietic agents, monoclonal antibodies, anti‐cancer and anti‐viral agents, antipsychotic, cardiovascular, and sedative/hypnotic agents. Dr. Mould is involved in clinical trial simulation and optimal study design in drug development. She was a member of the Scientific Advisory Group for PharSight, where she assisted in development of clinical trial simulation software.

Currently, Dr. Mould is President of Projections Research Inc., a consulting company offering pharmacokinetic and pharmacometric services. She is also the founder of Baysient LLC, a company that develops systems to individualize doses of drugs that are difficult to manage. She has published 88 peer‐reviewed articles, 18 chapters, made 104 national and international presentations, and presented 6 podium sessions on advanced modeling and simulation approaches. Dr. Mould has authored 105 posters at both national and international meetings. She is an adjunct professor at the University of Rhode Island, OSU, and the University of Florida, and teaches an annual class on disease progression modeling at the National Institutes of Health. Dr Mould taught nine courses (OSU, URI, and SUNY Buffalo) on specialized aspects of population pharmacokinetic and dynamic modeling. She is a member of the editorial board for Journal of Pharmacokinetics and Pharmacodynamics, Clinical Pharmacology and Therapeutics, and Clinical Pharmacology and Therapeutics Pharmacometrics and Systems Pharmacology. Dr. Mould is a Fellow of the ACCP and of the American Association of Pharmaceutical Sciences (AAPS).

Therapeutic proteins have emerged as a critical class of medicines for treating a wide range of chronic, serious, and/or life‐threatening manifestations in dermatology, immunology, musculoskeletal disorders, oncology, pulmonary/respiratory diseases, rheumatology, and urology. The Food and Drug Administration (FDA) has approved more than 80 therapeutic proteins between January 2011 and May 2018. Monoclonal antibodies (mAbs) have accounted for nearly 50% of FDA approvals [1,2]. Other regulatory agencies in Europe and Asia have followed a similar trajectory of approvals. As a group, biologics designed to treat inflammatory diseases target tumor necrosis factor (TNF) and other proinflammatory cytokines or immune competent molecules that are responsible for the initiation and propagation of inflammation and immunity.

This book focuses on immune‐mediated inflammatory diseases (IMID). This category of disease includes over 100 different adult and pediatric clinical phenotypes that share common inflammatory etiologies and pathways. The most common IMID are ulcerative colitis, Crohn's disease, rheumatoid arthritis, psoriasis, and systemic lupus erythematosus (SLE). The prevalence of IMID in the general population is estimated to be 10%. When left untreated or treated less than optimally with various therapeutic proteins, IMID can progress and lead to significant tissue damage, disability, reduced quality of life, and increased mortality. In addition, nonadherence (estimated to be 50%) to prescribed therapeutic proteins because of the lack of benefit or occurrence of adverse drug events is a major burden to health‐care systems resulting in disease reoccurrence, costly emergency room visits, extended hospitalizations, and necessary surgeries.

The introduction of therapeutic proteins into clinical practice as monotherapies or as part of combination treatments has been a godsend for patients with IMID. However, while therapeutic proteins have revolutionized the way that IMID are treated, these therapies remain an enigma. We do not fully understand the underlying pharmacological mechanisms to explain why 30–40% of patients do not respond to therapy. Assuming 100% adherence, it is compelling to think that a better mechanistic understanding of the causes of high inter‐individual and inter‐occasion variability in pharmacokinetic (PK) and/or pharmacodynamic (PD), as well as the predictable development of neutralizing or binding and nonneutralizing antidrug antibodies (ADA), would be an effective quantitative strategy to address suboptimal dosing in both drug development and clinical practice.

Given that molecules of biological origin are one of the most innovative and rapidly growing areas of pharmaceutical drug development, representing 45% of active pipeline drugs in 2017 [3], it is incumbent for scientists and clinicians in the pharmaceutical industry and regulatory agencies, as well as in academia, to provide the necessary data (bioinformatics) and mathematical tools to explore the data (analytics) with the goal of developing and implementing model‐based individualized treatment strategies for patients receiving therapeutic proteins for IMID. Model Informed Drug Development (MIDD) and its integration into drug development and New Drug Applications is a major goal of the FDA under the Prescription Drug User Fee Act for fiscal years 2018–2022 (PDUFA VI). In addition, personalized medicine represents a new treatment paradigm for therapeutic proteins, and more than 20% of all new molecular entities approved by FDA in 2016 were classified as personalized medicines and rely on DNA‐based safety and efficacy biomarkers. It is expected that there will be a 69% increase in the number of personalized therapies by 2020 [4].

Therapeutic proteins are complex moieties. It has been over a decade since the publication of one of the earliest books on the clinical pharmacology of therapeutic proteins [5]. A more recent book dealt comprehensively with the basic principles of absorption, distribution, metabolism, and excretion (ADME), and PK/PD of therapeutic proteins [6]. While not a primary emphasis, this book did introduce the basic concepts of mechanistic physiologically based pharmacokinetic (PBPK) models and the use of PK/PD models to inform therapeutic protein research and development.

By contrast, this book is a natural extension of those earlier books and focuses greater attention on a very thorough discussion of the contemporary and timely topic of quantitative pharmacology (QP) and individualized treatment strategies for therapeutic proteins in IMID. The editors and authors recognize the complex nature of PK/PD relationships of therapeutic proteins and individual chapters delve into these relationships in detail with an eye toward MIDD strategies. The book is a benchmark description of the state‐of‐the‐art in QP and represents a definitive work with an impressive 18 chapters covering a wide range of topics from the pathophysiology of autoimmune diseases to a reference source for biomarkers in ulcerative colitis, to model‐based precision dosing in inflammatory bowel diseases. The authors are well‐known experts in therapeutic proteins representing leading academic research centers, specialized contract research organizations, and pharmaceutical industries whose pipelines include therapeutic proteins. Rather than reiterating the basic clinical pharmacology principles appearing in the earlier books on therapeutic proteins, this book rightly focuses on advanced applications of pharmacometrics (modeling and simulation) and systems pharmacology to the development of these biologicals. This is a welcomed and needed addition to the field because the past 10 years have witnessed a significant benefit of implementing QP in the development of small molecules, but the field has neglected to a large degree similar integration of QP tools and techniques into the development of new biologicals. A noteworthy addition to this book is the four chapters on case examples of using QP for therapeutic proteins in plaque psoriasis, inflammatory bowel disease, SLE, and multiple sclerosis that provides a “sharing” of practical experiences in applying QP. The case examples also illustrate a useful “how to” approach to addressing drug development questions using QP unique to the drug classes selected for the cases. The book is weighted toward QP in drug development with less discussion of model‐based individualized dosing strategies based on PK/PD relationships. However, one can anticipate that decision support tools for individualizing therapeutic protein dosing will flourish as more and more core data on systemic and site‐of‐action PK and PD, and the influence of ADA formation become available to support point‐of‐care software development.

In short, this book is ideal for graduate students and postdoctoral research associates who are in training for careers in QP, advanced pharmacometrics scientists, or model‐oriented clinicians in industry, regulatory, or academia who already have a fundamental grasp of the ADME and clinical uses of therapeutic proteins but wish to learn more about how QP technologies (e.g., PBPK, model‐based meta‐analysis, population exposure‐response modeling) can be applied to optimize development and individualized dosing of therapeutic proteins.

I have been a long‐standing advocate for integrating the principles of MIDD into drug development and regulatory decision‐making during my 17‐year tenure as Director of the FDA's Office of Clinical Pharmacology. I can easily imagine that this book will provide not only a blueprint for greater integration of QP into the development and use of therapeutic proteins, but also a catalyst to match the energy and benefits that QP has brought to small molecule drug development and individualized dosing for the past 10–15 years. By applying the knowledge embodied in this book, one will achieve a much better understanding of therapeutic proteins and diseases that are treated by them. QP in particular will give rise to a greater awareness of optimized dosing, model‐informed clinical trial design, support of efficacy, predicting clinical outcomes, evaluating safety and adverse events and mechanistic support of dosing in children in pediatric IMID. It will be of great value to opinion‐leaders in the profession.

References

1. 1 HAD, L., Alexaki, A., Simhadri, V.L. et al. (2017). Recent advances in therapeutic protein drug development. F1000Res https://doi.org/10.12688/f1000research.9970.1.
2. 2 CenterWatch. https://centerwatch.com/drug‐information/FDA‐approved‐drugs/year/2017and2018.
3. 3 Pharma Intelligence (2017). Pharma R&D Annual Review 2017. Pharmaprojects, Informa UK Ltd.
4. 4 The Biopharmaceutical Pipeline (2017). Innovative Therapies in Clinical Development. Boston, MA: The Analysis Group.
5. 5 Mahmood, I. (ed.) (2006). Clinical Pharmacology of Therapeutic Proteins. Rockville, MD: Pine House Publishers.
6. 6 Zhou, H. and Theil, F.‐P. (eds.) (2015). ADME and Translational Pharmacokinetics/Pharmacodynamics of Therapeutic Proteins. Wiley.

Over the past two decades, protein therapeutics, and especially monoclonal antibodies, have transformed the management of autoimmune diseases and the lives of people with those diseases. For many patients, the dreadful symptoms of autoimmune arthritis, inflammatory bowel diseases, plaque psoriasis, and other diseases have been substantially alleviated and the disabling destruction of diseases such as rheumatoid arthritis have been slowed or halted. These remarkable medical advances resulted from substantial work in many scientific, medical, and engineering disciplines, including quantitative pharmacology and modeling. Far beyond the critical efforts of understanding pathophysiologic mechanisms and designing therapeutic interventions, hard‐won progress also required understanding the determinants of the pharmacokinetics and the immunogenicity of protein therapeutics, engineering molecules to optimize these characteristics, developing dosing and therapeutic regimens to exploit them, and identifying and utilizing biomarkers (e.g. c‐reactive protein) to guide development and assess effects.

Notwithstanding these remarkable successes, much remains to be done. Responses to protein therapeutics are usually less than complete, some patients do not respond at all while others have to be cycled through a variety of medicines to identify one which will help. Understanding why many individuals do not respond well and addressing the needs of those individuals is critically important. Prevention and early intervention remain largely a dream. On the safety side, avoiding the increased risks of infection and malignancy resulting from immunosuppression while still suppressing destructive autoimmune processes remains a daunting problem.

Challenging as these problems are, there is strong reason to believe that the tremendous rate of progress in the management of autoimmune disease with protein therapeutics will continue. The diversity of protein therapeutics is limitless, their potential is extraordinary, and strong pharmacologic science with interdisciplinary collaboration remains the key to realizing that potential. This book highlights many of the critical areas of research and key projects that will help ensure decades more of major advances in the management of autoimmune disease with protein therapeutics.