This book describes the principles, methods, and applications of PBPK modeling in the pharmaceutical industry. It addresses a growing need, as more and more pharma companies are integrating PBPK into their lead selection cycle and clinical development. Moving easily from theory to practice, the author presents coverage of both the principles and applications of PBPK modeling, exposing the power of this tool to improve the process of drug discovery and development. With end-of-chapter glossaries, extensive bibliographic references, and an emphasis on practical applications, this resource provides a much-needed single source for this important area.
| ISBN | 0470484063 | | Pages | 448 | | ISBN13 | 9780470484067
(What's this?) | | Weight (grammes) | 750 | | Publisher | John Wiley and Sons Ltd | | Published in | Chicester | | Imprint | Wiley-Blackwell (an imprint of John Wiley & Sons Ltd) | | Height (mm) | 232 | | Format | Hardback | | Width (mm) | 165 | | Publication date | 27 Mar 2012 | | Spine width (mm) | 32 | | DEWEY | 615.7 | | Academic level | Professional / Scholarly | | DEWEY edition | DC23 | |
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Preface xv Acknowledgments xvii SECTION I. PRINCIPLES AND METHODS 1 1 MODELING IN THE PHARMACEUTICAL INDUSTRY 3 1.1 Introduction 3 1.2 Modeling Approaches 4 1.3 Steps Needed to Maximize Effective Integration of Models into R&D Workflow 7 1.4 Scope of the Book 8 Keywords 10 References 12 2 PHYSIOLOGICALLY-BASED MODELING 13 2.1 Introduction 13 2.2 Examples of Physiological Modeling 14 2.3 Need for Physiological Models in the Pharmaceutical Industry 15 2.4 Organs as Compartments 15 2.5 Bottom-Up vs. Top-Down Modeling in Pharmacokinetics 16 References 16 3 REVIEW OF PHARMACOKINETIC PRINCIPLES 17 3.1 Introduction 18 3.2 Routes of Administration 18 3.3 Drug Disposition 18 3.3.1 Absorption 18 3.3.2 Plasma Protein Binding, BloodPlasma Ratio 20 3.3.3 Distribution, Elimination, Half-Life, and Clearance 23 3.3.4 Role of Transporters in ADME 29 3.4 Linear and Nonlinear Pharmacokinetics 34 3.5 Steady-State Pharmacokinetics 34 3.6 Dose Estimations 37 3.7 Successful PK Optimization in Drug Discovery 40 Keywords 40 References 41 4 PHYSIOLOGICAL MODEL FOR ABSORPTION 43 4.1 Introduction 44 4.2 Drug Absorption and Gut Bioavailability 44 4.2.1 Solubility and Dissolution Rate 44 4.2.2 Permeability: Transcelluar, Paracellular, and Carrier-Mediated Pathways 51 4.2.3 Barriers to Membrane Transport-Luminal Degradation, Efflux, and Gut Metabolism 53 4.3 Factors Affecting Drug Absorption and Gut Bioavailability 56 4.3.1 Physiological Factors Affecting Oral Drug Absorption and Species Differences in Physiology 56 4.3.2 Compound-Dependent Factors 62 4.3.3 Formulation-Dependent Factors 63 4.4 In Silico Predictions of Passive Permeability and Solubility 66 4.4.1 In Silico Models for Permeability 66 4.4.2 In Silico Models for Solubility 67 4.5 Measurement of Permeability, Solubility, Luminal Stability, Efflux, and Intestinal Metabolism 67 4.5.1 In Vitro, in Situ and in Vivo Assays for Permeability 67 4.5.2 Measurement of Thermodynamic or Equilibrium Solubility 72 4.5.3 Luminal Stability 74 4.5.4 Efflux 74 4.5.5 In Vitro Models for Estimating Extent of Gut Metabolism 76 4.6 Absorption Modeling 76 Keywords 83 References 84 5 PHYSIOLOGICAL MODEL FOR DISTRIBUTION 89 5.1 Introduction 90 5.2 Factors Affecting Tissue Distribution of Xenobiotics 91 5.2.1 Physiological Factors and Species Differences in Physiology 91 5.2.2 Compound-Dependent Factors 98 5.3 In Silico Models of Tissue Partition Coefficients 98 5.4 Measurement of Parameters Representing Rate and Extent of Tissue Distribution 105 5.4.1 Assessment of Rate and Extent of Brain Penetration 105 5.5 Physiological Model for Drug Distribution 110 5.6 Drug Concentrations at Site of Action 111 Keywords 114 References 115 6 PHYSIOLOGICAL MODELS FOR DRUG METABOLISM AND EXCRETION 119 6.1 Introduction 119 6.2 Factors Affecting Drug Metabolism and Excretion of Xenobiotics 120 6.3 Models for Hepatobiliary Elimination and Renal Excretion 124 6.3.1 In Silico Models 124 6.3.2 In Vitro Models for Hepatic Metabolism 125 6.3.3 In Vitro Models for Transporters 127 6.4 Physiological Models 136 6.4.1 Hepatobiliary Elimination of Parent Drug and Metabolites 136 6.4.2 Renal Excretion 141 References 144 7 GENERIC WHOLE-BODY PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELING 153 7.1 Introduction 153 7.2 Structure of a Generic Whole Body PBPK Model 154 7.3 Model Assumptions 157 7.4 Commercial PBPK Software 158 References 159 8 VARIABILITY, UNCERTAINTY, AND SENSITIVITY ANALYSIS 161 8.1 Introduction 161 8.2 Need for Uncertainty Analysis 162 8.3 Sources of Physiological, Anatomical, Enzymatic, and Transporter Variability 163 8.4 Modeling Uncertainty and Population Variability with Monte Carlo Simulations 169 8.5 Sensitivity Analysis 172 8.6 Conclusions 174 Keywords 174 References 175 9 EVALUATION OF DRUGDRUG INTERACTION RISK WITH PBPK MODELS 183 9.1 Introduction 184 9.2 Factors Affecting DrugDrug Interactions 186 9.3 In Vitro Methods to Evaluate DrugDrug Interactions 190 9.3.1 Candidate Drug as a Potential Inhi
"Peters does a credible job of bringing this huge area of complex physiology and mathematics together." ( Pharmaceutical Journal , 21 July 2012)
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