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.