Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations. Sheila Annie Peters

logistics issues, and confounding disease influence on outcomes. Along with World Health Organization's SOLIDARITY trial and Institut national de la santé et de la recherche médicale (INSERM)'s Discovery trial, nearly thousand clinical studies related to COVID‐19 have been registered worldwide in the first half of 2020. In a race against time to bring innovative medicines to the market, a heightened need for Model‐Informed Drug Development (MIDD) and the totality of evidence it advocates has become apparent. The applications of PBPK modeling, an important component of MIDD, supporting dose optimization and assessment of benefit‐risk ratios have been further catalyzed by the pandemic.

      The book is intended to serve the interests of a broad and diverse audience from academia, industry, and regulatory agencies. Similar to the first edition of the book, this second edition has a section that covers the principles underlying pharmacokinetics, drug interactions, and physiological modeling of pharmacokinetic processes as well as interindividual variability for small molecule drugs and biologics. The second part exposes the reader to the powerful applications of PBPK modeling along the value chain in drug discovery and development. To facilitate potential use of the book in courses or workshops, a new third section providing case studies in the different areas of application of PBPK modeling has been introduced in this edition at the request of readers and reviewers. Most of these case studies are built using PK‐Sim®, a comprehensive software tool within the Open Systems Pharmacology Suite for the physiologically based pharmacokinetic modeling of small and large molecules.

In addition to introducing a third section to the book, this second edition simplifies complex topics and provides a balanced view of the vast potential of PBPK modeling alongside current challenges. Section‐I provides substantially revised and reordered content with updated literature in all chapters. A new chapter has been added on Nonclinical, Clinical and Model Informed Drug Development. Chapters in Section‐II are entirely new and focus on the vast array of applications in the field. Two‐thirds of the figures in the second edition are either revised or new.

      I hope that the inclusion of recent advances in PBPK modeling and the revisions made in the current edition will serve to benefit and engage the readers.

      PREFACE TO THE FIRST EDITION

      Physiologically-based pharmacokinetic (PBPK) modelling has made rapid strides in the pharmaceutical industry in the last decade or so, thanks to an increasing awareness of the potential applications of this powerful tool. As pharmaceutical companies are working to integrate PBPK modelling into their lead selection cycle and clinical development, the availability of commercial software has played a key role in enabling even those without modelling expertise to come on board. However, this entails the risk of misuse, misinterpretation or over-interpretation of modelling results, if the principles and underlying assumptions of PBPK modelling are not clearly understood by the users. Today, the challenge facing pharmaceutical companies is educating and training their staff to achieve an effective application of PBPK/PD in projects across the value chain. In the future, providers of education should take on the responsibility of making available, modellers with appropriate skills. Given the complexity of PBPK modelling, it is certainly not an easy task for a beginner with little or no background to understand the model structure and to be aware of its limitations. The lack of a text book on PBPK has been a further deterrent. It is hoped that the book will serve as a primary source of information on the principles, methods and applications of PBPK modelling, exposing the power of a largely hidden and unexplored tool. Applications in the pharma sector will be the main focus, as applications in environmental toxicology and human health risk assessment, have already been the subject of a previous publication.

      Target audiences for the book include students and researchers in the academia, apart from scientists and modellers in the pharmaceutical industry. The book can also be a resource for R&D managers in the pharmaceutical industry, seeking a quick overview of the benefits of applying PBPK modelling along the drug discovery and development value chain. An understanding of the principles of PBPK modelling by R&D management would enhance their acceptance and appreciation, which in turn can translate to effective managerial support for PBPK modelling. The book is intended to serve the interests of both the general reader, who may only want an overview of the applications of PBPK modelling without wanting an in-depth understanding of the underlying methods, and the specialist reader who may be interested to build new models. For the general reader, keywords highlighted in capitals are explained at the end of the chapters. No particular expertise is assumed in order to keep the book accessible to a diverse audience. An extensive list of bibliographic references will help the specialist reader to build on the concepts developed in the book. A generous use of figures to illustrate concepts will help the reader to gain valuable insights into this fascinating subject.

      The book comprises two parts. The first part provides a detailed and systematic treatment of the principles behind physiological modelling of pharmacokinetic processes, inter-individual variability and drug interactions for small molecule drugs and biologics. The second part exposes the reader to the powerful applications of PBPK modelling along the value chain in drug discovery and development.

      ACKNOWLEDGMENTS

      My sincere thanks are due to Prof. Amin Rostami‐Hodjegan who reviewed chapters of the book relating to applications of PBPK modeling, despite other demands on his time. Being at the forefront of research in the field of PBPK modeling, his suggestions were very valuable in structuring the content and updating the chapters with the latest developments in the area. I am grateful to Adam Darwich, Nicola Melillo, Dan Liu, and Alexander Cooper whose help with reviewing my chapters is greatly appreciated. I would like to thank my colleagues at Merck Healthcare KGaA, Joao NS Pereira, Ulrike Graadhand, Andreas D Becker, and Akash Khandelwal who also helped review some of the chapters, and Rainer Strotmann for letting me use some figures he created. My deep appreciation goes to Christina Peters for finding time in the midst of her busy career to create some excellent figures for this edition. I would like to acknowledge the enthusiastic support I received from Vignesh Murugesan for gathering some data for the book. I am extremely grateful to Jan Schlender, Annika Schneider, and Michael Krug, who over the last two years, devoted their time to creating the case studies in PK‐Sim as well as HELP manuals. This work would not have been possible without the consistent support extended by my friends and family.

      ABOUT THE COMPANION WEBSITE

      This book is accompanied by a companion website

       www.wiley.com/go/peters/PBPK_modeling_simulations

      The website includes case studies.

SECTION I PRINCIPLES, METHODS AND BACKGROUND INFORMATION

1 A REVIEW OF PHARMACOKINETIC AND PHARMACODYNAMIC PRINCIPLES

      CONTENTS

      1  1.1 Introduction

      2  1.2 Pharmacokinetic Principles 1.2.1 Routes of Drug Administration 1.2.2 Intravenous Bolus 1.2.3 Plasma Protein Binding and Blood–Plasma Ratio