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.
1 A REVIEW OF PHARMACOKINETIC AND PHARMACODYNAMIC PRINCIPLES
CONTENTS
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 1.2.4 Hepatic, Renal, and Biliary Clearances 1.2.5 Extravascular (Subcutaneous, Intramuscular, and Per Oral) Absorption 1.2.6 Absorption from Solid Dosage Forms 1.2.7 Role of Transporters in ADME 1.2.8 Linear and Non‐Linear Pharmacokinetics 1.2.9 Intravenous Infusion, Repeated Dosing, Steady State Kinetics, and Accumulation 1.2.10 Active Metabolite and Prodrug Kinetics
3 1.3 Pharmacokinetic Variability
4 1.4 Pharmacokinetics Optimization in Drug Discovery
5 1.5 Pharmacodynamic Principles 1.5.1 Pharmacological Targets and Drug Action 1.5.2 Functional Adaptation Processes 1.5.3 Biomarkers, Surrogate Endpoints, and Clinical Endpoints Keywords References
1.1 INTRODUCTION
The dose and dosing frequency of a drug (dosage regimen), needed to maintain an efficacious concentration at the site of its pharmacological action, for a duration that is long enough to achieve the therapeutic objective, should be safe and convenient to the patient. To achieve this optimal exposure at
