Physiologically-Based Pharmacokinetic (PBPK) Modeling and Simulations: Principles, Methods, and Applications in the Pharmaceutical Industry ist das einzige Buch seiner Art, das sich an die schnell wachsende Gemeinschaft der PBPK-Anwender richtet und in klaren, prägnanten Worten die Grundlagen darstellt. Durch die Verbindung von Theorie und Praxis wird in diesem Werk das unglaubliche Potenzial der PBPK-Modellierung für die Verbesserung der Entdeckung und Entwicklung von Arzneimitteln betrachtet. In der neuen Ausgabe wird der Schwerpunkt stärker auf Anwendungen und relevante Fallstudien gelegt.…mehr
Physiologically-Based Pharmacokinetic (PBPK) Modeling and Simulations: Principles, Methods, and Applications in the Pharmaceutical Industry ist das einzige Buch seiner Art, das sich an die schnell wachsende Gemeinschaft der PBPK-Anwender richtet und in klaren, prägnanten Worten die Grundlagen darstellt. Durch die Verbindung von Theorie und Praxis wird in diesem Werk das unglaubliche Potenzial der PBPK-Modellierung für die Verbesserung der Entdeckung und Entwicklung von Arzneimitteln betrachtet. In der neuen Ausgabe wird der Schwerpunkt stärker auf Anwendungen und relevante Fallstudien gelegt. Außerdem gibt es eine begleitende Website mit Datensätzen, die viele der wichtigsten Entwicklungen im Bereich der PBPK-Modellierung und -Simulation seit der Veröffentlichung der ersten Ausgabe im Jahr 2012 abbilden.
Sheila Annie Peters, PhD, is Head of Translational Quantitative Pharmacology at Merck Healthcare, Darmstadt, Germany. Previously, she was an Associate Principal Scientist for Discovery DMPK and Bioanalytical Chemistry at AstraZeneca and Principal Scientist at Cyprotex Discovery. She has lectured at the Regional Engineering College (Trichy, India) and University of Madras and Pondicherry University.
Inhaltsangabe
Preface xix
Acknowledgements xxi
About the companion xxiii
Section I. Principles, Methods, andBackground Information 1
1 A Review of Pharmacokinetic and Pharmacodynamic Principles 3
1.1 Introduction 4
1.2 Pharmacokinetic Principles 4
1.2.1 Routes of Drug Administration 4
1.2.2 Intravenous Bolus 4
1.2.3 Plasma Protein Binding and Blood-Plasma Ratio 9
1.2.4 Hepatic, Renal, and Biliary Clearances 12
1.2.5 Extravascular (Subcutaneous, Intramuscular, and Per Oral) Absorption 16
1.2.6 Absorption from Solid Dosage Forms 20
1.2.7 Role of Transporters in ADME 22
1.2.8 Linear and Non-Linear Pharmacokinetics 24
1.2.9 Intravenous Infusion, Repeated Dosing, Steady State Kinetics, and Accumulation 25
1.2.10 Active Metabolite and Prodrug Kinetics 28
1.3 Pharmacokinetic Variability 32
1.4 Pharmacokinetics Optimization in Drug Discovery 34
1.5 Pharmacodynamic Principles 34
1.5.1 Pharmacological Targets and Drug Action 35
1.5.2 Functional Adaptation Processes 39
1.5.3 Biomarkers, Surrogate Endpoints, and Clinical Endpoints 41
Keywords 47
References 48
2 A Review of Drug-Drug Interactions 51
2.1 Introduction 51
2.2 Drug Interactions Mediated by Enzymes and Transporters at Various Sites 54
2.3 Factors Affecting DDI 54
2.4 In Vitro Methods to Evaluate Drug-Drug Interactions 56
2.4.1 Candidate Drug as a Potential Perpetrator 57
2.4.2 Candidate Drug as a Potential Victim of Inhibition 58
2.5 Sources of Uncertainty 59
2.6 Therapeutic Protein-Drug Interaction 59
References 61
3 Modeling Pharmacokinetics, Pharmacodynamics, And Drug Interactions 65
3.1 Introduction 66
3.2 Modeling Pharmacokinetics 66
3.2.1 Compartmental Modeling of Linear and Nonlinear Pharmacokinetics (Enzyme and/or Transporter Capacity Limitation as Well as Target-Mediated Drug Disposition) 67
3.2.2 Population Pharmacokinetics 76
3.3 Pharmacokinetics/Pharmacodynamics and PK/Efficacy (Exposure/ Response) Modeling 80
3.3.1 PK/PD Models for Direct Effect: Sigmoid Emax Model 84
3.3.2 PK/PD Models for Direct Effect: Classical Receptor Theory 86
Section I. Principles, Methods, andBackground Information 1
1 A Review of Pharmacokinetic and Pharmacodynamic Principles 3
1.1 Introduction 4
1.2 Pharmacokinetic Principles 4
1.2.1 Routes of Drug Administration 4
1.2.2 Intravenous Bolus 4
1.2.3 Plasma Protein Binding and Blood-Plasma Ratio 9
1.2.4 Hepatic, Renal, and Biliary Clearances 12
1.2.5 Extravascular (Subcutaneous, Intramuscular, and Per Oral) Absorption 16
1.2.6 Absorption from Solid Dosage Forms 20
1.2.7 Role of Transporters in ADME 22
1.2.8 Linear and Non-Linear Pharmacokinetics 24
1.2.9 Intravenous Infusion, Repeated Dosing, Steady State Kinetics, and Accumulation 25
1.2.10 Active Metabolite and Prodrug Kinetics 28
1.3 Pharmacokinetic Variability 32
1.4 Pharmacokinetics Optimization in Drug Discovery 34
1.5 Pharmacodynamic Principles 34
1.5.1 Pharmacological Targets and Drug Action 35
1.5.2 Functional Adaptation Processes 39
1.5.3 Biomarkers, Surrogate Endpoints, and Clinical Endpoints 41
Keywords 47
References 48
2 A Review of Drug-Drug Interactions 51
2.1 Introduction 51
2.2 Drug Interactions Mediated by Enzymes and Transporters at Various Sites 54
2.3 Factors Affecting DDI 54
2.4 In Vitro Methods to Evaluate Drug-Drug Interactions 56
2.4.1 Candidate Drug as a Potential Perpetrator 57
2.4.2 Candidate Drug as a Potential Victim of Inhibition 58
2.5 Sources of Uncertainty 59
2.6 Therapeutic Protein-Drug Interaction 59
References 61
3 Modeling Pharmacokinetics, Pharmacodynamics, And Drug Interactions 65
3.1 Introduction 66
3.2 Modeling Pharmacokinetics 66
3.2.1 Compartmental Modeling of Linear and Nonlinear Pharmacokinetics (Enzyme and/or Transporter Capacity Limitation as Well as Target-Mediated Drug Disposition) 67
3.2.2 Population Pharmacokinetics 76
3.3 Pharmacokinetics/Pharmacodynamics and PK/Efficacy (Exposure/ Response) Modeling 80
3.3.1 PK/PD Models for Direct Effect: Sigmoid Emax Model 84
3.3.2 PK/PD Models for Direct Effect: Classical Receptor Theory 86
