{"product_id":"physiologically-based-pharmacokinetic-pbpk-modeling-and-simulations-isbn-9781119497684","title":"Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations","description":"\u003cb\u003ePhysiologically Based Pharmacokinetic (PBPK) Modeling and Simulations\u003c\/b\u003e \u003cp\u003e\u003cb\u003eThe first book dedicated to the emerging field of physiologically based pharmacokinetic modeling (PBPK)\u003c\/b\u003e \u003c\/p\u003e\u003cp\u003eNow in its second edition, \u003ci\u003ePhysiologically Based Pharmacokinetic (PBPK) Modelling and  Simulations: Principles, Methods, and Applications in the Pharma Industry\u003c\/i\u003e remains the premier reference book throughout the rapidly growing PBPK user community. Using clear and concise language, author Sheila Annie Peters connects theory with practice as she explores the vast potential of PBPK modeling for improving drug discovery and development. \u003c\/p\u003e\u003cp\u003eThis fully updated new edition covers key developments in the field of PBPK modelling and simulations that have emerged in recent years. A brand-new section provides case studies in different application areas of PBPK modelling, including drug-drug interaction, genetic polymorphism, renal impairment, and pediatric extrapolation. Additional chapters address  topics such as model-informed drug development (MIDD) and expose readers to a wide range of  current applications in the field. Throughout the book, substantially revised  chapters simplify complex topics and offer a balanced view of both the opportunities and challenges of PBPK modelling. Providing timely and comprehensive coverage of one of the most exciting new areas of pharmaceutical science, this book: \u003c\/p\u003e\u003cul\u003e\n\u003cli\u003eDescribes the principles behind physiological modeling of pharmacokinetic processes, inter-individual variability, and drug interactions for small molecule drugs and biologics\u003c\/li\u003e \u003cli\u003eFeatures a wealth of new figures and case studies of the applications of PBPK modelling along the value chain in drug discovery and development\u003c\/li\u003e \u003cli\u003eReflects the latest regulatory guidelines on the reporting of PBPK modelling analysis\u003c\/li\u003e \u003cli\u003eIncludes access to a new companion website containing code, datasets, explanations of case examples in the text, and discussion of key developments in the field\u003c\/li\u003e \u003cli\u003eContains a brief overview of the field, end-of-chapter keywords for easy reference, and an extensive bibliography\u003c\/li\u003e\n\u003c\/ul\u003e \u003cp\u003e\u003ci\u003ePhysiologically Based Pharmacokinetic (PBPK) Modeling and Simulations: Principles, Methods, and Applications in the Pharmaceutical Industry, Second Edition\u003c\/i\u003e is an indispensable ­single-volume resource for beginning and intermediate practitioners across the pharmaceutical sciences in both industry and academia.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. \u003c\/p\u003e\u003cp\u003ePreface xix\u003c\/p\u003e \u003cp\u003eAcknowledgements xxi\u003c\/p\u003e \u003cp\u003eAbout the companion xxiii\u003c\/p\u003e \u003cp\u003e\u003cb\u003eSection I. Principles, Methods, and\u003c\/b\u003e\u003cb\u003eBackground Information 1\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e1 A Review of Pharmacokinetic and Pharmacodynamic\u003c\/b\u003e \u003cb\u003ePrinciples 3\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e1.1 Introduction 4\u003c\/p\u003e \u003cp\u003e1.2 Pharmacokinetic Principles 4\u003c\/p\u003e \u003cp\u003e1.2.1 Routes of Drug Administration 4\u003c\/p\u003e \u003cp\u003e1.2.2 Intravenous Bolus 4\u003c\/p\u003e \u003cp\u003e1.2.3 Plasma Protein Binding and Blood–Plasma Ratio 9\u003c\/p\u003e \u003cp\u003e1.2.4 Hepatic, Renal, and Biliary Clearances 12\u003c\/p\u003e \u003cp\u003e1.2.5 Extravascular (Subcutaneous, Intramuscular, and Per Oral) Absorption 16\u003c\/p\u003e \u003cp\u003e1.2.6 Absorption from Solid Dosage Forms 20\u003c\/p\u003e \u003cp\u003e1.2.7 Role of Transporters in ADME 22\u003c\/p\u003e \u003cp\u003e1.2.8 Linear and Non-Linear Pharmacokinetics 24\u003c\/p\u003e \u003cp\u003e1.2.9 Intravenous Infusion, Repeated Dosing, Steady State Kinetics, and Accumulation 25\u003c\/p\u003e \u003cp\u003e1.2.10 Active Metabolite and Prodrug Kinetics 28\u003c\/p\u003e \u003cp\u003e1.3 Pharmacokinetic Variability 32\u003c\/p\u003e \u003cp\u003e1.4 Pharmacokinetics Optimization in Drug Discovery 34\u003c\/p\u003e \u003cp\u003e1.5 Pharmacodynamic Principles 34\u003c\/p\u003e \u003cp\u003e1.5.1 Pharmacological Targets and Drug Action 35\u003c\/p\u003e \u003cp\u003e1.5.2 Functional Adaptation Processes 39\u003c\/p\u003e \u003cp\u003e1.5.3 Biomarkers, Surrogate Endpoints, and Clinical Endpoints 41\u003c\/p\u003e \u003cp\u003eKeywords 47\u003c\/p\u003e \u003cp\u003eReferences 48\u003c\/p\u003e \u003cp\u003e\u003cb\u003e2 A Review of Drug–Drug Interactions 51\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e2.1 Introduction 51\u003c\/p\u003e \u003cp\u003e2.2 Drug Interactions Mediated by Enzymes and Transporters at Various Sites 54\u003c\/p\u003e \u003cp\u003e2.3 Factors Affecting DDI 54\u003c\/p\u003e \u003cp\u003e2.4 In Vitro Methods to Evaluate Drug–Drug Interactions 56\u003c\/p\u003e \u003cp\u003e2.4.1 Candidate Drug as a Potential Perpetrator 57\u003c\/p\u003e \u003cp\u003e2.4.2 Candidate Drug as a Potential Victim of Inhibition 58\u003c\/p\u003e \u003cp\u003e2.5 Sources of Uncertainty 59\u003c\/p\u003e \u003cp\u003e2.6 Therapeutic Protein–Drug Interaction 59\u003c\/p\u003e \u003cp\u003eReferences 61\u003c\/p\u003e \u003cp\u003e\u003cb\u003e3 Modeling Pharmacokinetics, Pharmacodynamics, And\u003c\/b\u003e \u003cb\u003eDrug Interactions 65\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e3.1 Introduction 66\u003c\/p\u003e \u003cp\u003e3.2 Modeling Pharmacokinetics 66\u003c\/p\u003e \u003cp\u003e3.2.1 Compartmental Modeling of Linear and Nonlinear Pharmacokinetics (Enzyme and\/or Transporter Capacity Limitation as Well as Target-Mediated Drug Disposition) 67\u003c\/p\u003e \u003cp\u003e3.2.2 Population Pharmacokinetics 76\u003c\/p\u003e \u003cp\u003e3.3 Pharmacokinetics\/Pharmacodynamics and PK\/Efficacy (Exposure\/ Response) Modeling 80\u003c\/p\u003e \u003cp\u003e3.3.1 PK\/PD Models for Direct Effect: Sigmoid \u003ci\u003eE\u003csub\u003emax\u003c\/sub\u003e \u003c\/i\u003eModel 84\u003c\/p\u003e \u003cp\u003e3.3.2 PK\/PD Models for Direct Effect: Classical Receptor Theory 86\u003c\/p\u003e \u003cp\u003e3.3.3 PK\/PD Models Accommodating Delayed Pharmacological Response 89\u003c\/p\u003e \u003cp\u003e3.3.4 PK\/PD Models Accommodating Functional Adaptation Leading to Nonlinearity in Pharmacological Response with Respect to Time 96\u003c\/p\u003e \u003cp\u003e3.3.5 PK\/Efficacy Modeling 97\u003c\/p\u003e \u003cp\u003e3.3.6 Translation of PK\/PD and PK\/Efficacy Modeling to Human 100\u003c\/p\u003e \u003cp\u003e3.3.7 Average, Minimum, and Maximum Steady-State Concentrations 104\u003c\/p\u003e \u003cp\u003e3.3.8 Estimation of Biologically Effective Dose in Human 107\u003c\/p\u003e \u003cp\u003e3.3.9 Therapeutic Window 109\u003c\/p\u003e \u003cp\u003e3.3.10 Static Models for Drug Interactions 109\u003c\/p\u003e \u003cp\u003e3.4 Physiologically Based Pharmacokinetic (PBPK) Modeling and Its Integration with Pharmacodynamics and Efficacy Models 112\u003c\/p\u003e \u003cp\u003e3.4.1 PK Modeling Compartmental vs PBPK 112\u003c\/p\u003e \u003cp\u003e3.4.2 PK Variability: Population PK (popPK) Modeling vs PBPK 114\u003c\/p\u003e \u003cp\u003e3.4.3 Integration of PBPK with PD, Quantitative Systems Pharmacology (QSP) Models or Quantitative Systems Toxicologyand Safety (QSTS) 114\u003c\/p\u003e \u003cp\u003e3.4.4 PBPK Models to Evaluate Drug–Drug Interactions 115\u003c\/p\u003e \u003cp\u003e3.4.5 DDI Risk Assessment with PBPK vs Static Models 118\u003c\/p\u003e \u003cp\u003eKeywords 123\u003c\/p\u003e \u003cp\u003eReferences 125\u003c\/p\u003e \u003cp\u003e\u003cb\u003e4 Physiological Model For Absorption 129\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e4.1 Introduction 130\u003c\/p\u003e \u003cp\u003e4.2 Drug Absorption and Gut Bioavailability 130\u003c\/p\u003e \u003cp\u003e4.2.1 Solubility and Dissolution Rate 130\u003c\/p\u003e \u003cp\u003e4.2.2 Permeability: Transcellular, Paracellular, and Carrier-Mediated Pathways 136\u003c\/p\u003e \u003cp\u003e4.2.3 Barriers to Membrane Transport – Luminal Degradation, Efflux, and Gut Metabolism 138\u003c\/p\u003e \u003cp\u003e4.3 Factors Affecting Drug Absorption and Gut Bioavailability 140\u003c\/p\u003e \u003cp\u003e4.3.1 Physiological Factors Affecting Oral Drug Absorption and Species Differences in Physiology 140\u003c\/p\u003e \u003cp\u003e4.3.2 Compound-Dependent Factors 144\u003c\/p\u003e \u003cp\u003e4.3.3 Formulation-Dependent Factors 144\u003c\/p\u003e \u003cp\u003e4.4 \u003ci\u003eIn Silico \u003c\/i\u003ePredictions of Passive Permeability and Solubility 147\u003c\/p\u003e \u003cp\u003e4.4.1 \u003ci\u003eIn Silico \u003c\/i\u003eModels for Permeability 147\u003c\/p\u003e \u003cp\u003e4.4.2 \u003ci\u003eIn Silico \u003c\/i\u003eModels for Solubility 147\u003c\/p\u003e \u003cp\u003e4.5 Measurement of Permeability, Solubility, Luminal Stability, Efflux, Intestinal Metabolism 148\u003c\/p\u003e \u003cp\u003e4.5.1 \u003ci\u003eIn Vitro\u003c\/i\u003e, \u003ci\u003eIn Situ, \u003c\/i\u003eand \u003ci\u003eIn Vivo \u003c\/i\u003eModels for Effective Permeability 148\u003c\/p\u003e \u003cp\u003e4.5.2 Measurement of Thermodynamic or Equilibrium Solubility 153\u003c\/p\u003e \u003cp\u003e4.5.3 Luminal Stability 154\u003c\/p\u003e \u003cp\u003e4.5.4 Efflux 154\u003c\/p\u003e \u003cp\u003e4.5.5 \u003ci\u003eIn Vitro \u003c\/i\u003eModels for Gut Metabolism and Estimation of Fraction Escaping Gut Metabolism 155\u003c\/p\u003e \u003cp\u003e4.6 Absorption Modeling 156\u003c\/p\u003e \u003cp\u003eKeywords 162\u003c\/p\u003e \u003cp\u003eReferences 163\u003c\/p\u003e \u003cp\u003e\u003cb\u003e5 Physiological Model For Distribution 169\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e5.1 Introduction 170\u003c\/p\u003e \u003cp\u003e5.2 Factors Affecting Tissue Distribution of Xenobiotics 170\u003c\/p\u003e \u003cp\u003e5.2.1 Physiological Factors and Species Differences in Physiology 171\u003c\/p\u003e \u003cp\u003e5.2.2 Compound-Dependent Factors 176\u003c\/p\u003e \u003cp\u003e5.3 \u003ci\u003eIn Silico \u003c\/i\u003eModels of Tissue Partition Coefficients 176\u003c\/p\u003e \u003cp\u003e5.4 Measurement of Parameters Representing the Rate and Extent of Tissue Distribution 181\u003c\/p\u003e \u003cp\u003e5.4.1 Assessment of Rate and Extent of Brain Penetration 181\u003c\/p\u003e \u003cp\u003e5.5 Physiological Model for Drug Distribution 186\u003c\/p\u003e \u003cp\u003e5.6 Drug Concentrations at the Site of Action 187\u003c\/p\u003e \u003cp\u003eKeywords 189\u003c\/p\u003e \u003cp\u003eReferences 189\u003c\/p\u003e \u003cp\u003e\u003cb\u003e6 Physiological Models For Drug Metabolism And\u003c\/b\u003e \u003cb\u003eExcretion 193\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e6.1 Introduction 193\u003c\/p\u003e \u003cp\u003e6.2 Factors Affecting Drug Metabolism and Excretion of Xenobiotics 194\u003c\/p\u003e \u003cp\u003e6.3 Models for Hepatobiliary and Renal Excretion 197\u003c\/p\u003e \u003cp\u003e6.3.1 \u003ci\u003eIn Silico \u003c\/i\u003eModels 197\u003c\/p\u003e \u003cp\u003e6.3.2 \u003ci\u003eIn Vitro \u003c\/i\u003eModels for Hepatic Metabolism 197\u003c\/p\u003e \u003cp\u003e6.3.3 \u003ci\u003eIn Vitro \u003c\/i\u003eModels for Transporters 200\u003c\/p\u003e \u003cp\u003e6.4 Physiological Models 203\u003c\/p\u003e \u003cp\u003e6.4.1 Hepato-Biliary Elimination of Parent Drug and Metabolites 205\u003c\/p\u003e \u003cp\u003e6.4.2 Renal Excretion 208\u003c\/p\u003e \u003cp\u003eReferences 211\u003c\/p\u003e \u003cp\u003e\u003cb\u003e7 Generic Whole-Body Physiologically Based\u003c\/b\u003e \u003cb\u003ePharmacokinetic Modeling 217\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e7.1 Introduction 217\u003c\/p\u003e \u003cp\u003e7.2 Structure of a Generic Physiologically-Based Pharmacokinetic (PBPK) Model 218\u003c\/p\u003e \u003cp\u003e7.3 Somatic Compartments 220\u003c\/p\u003e \u003cp\u003e7.3.1 Lungs (\u003ci\u003eLU\u003c\/i\u003e) 220\u003c\/p\u003e \u003cp\u003e7.3.2 Arterial Blood \u003ci\u003e(ART\u003c\/i\u003e) 220\u003c\/p\u003e \u003cp\u003e7.3.3 Venous Blood (\u003ci\u003eVEN\u003c\/i\u003e) 220\u003c\/p\u003e \u003cp\u003e7.3.4 Stomach (\u003ci\u003eST\u003c\/i\u003e) 220\u003c\/p\u003e \u003cp\u003e7.3.5 Gut (\u003ci\u003eGU\u003c\/i\u003e) 220\u003c\/p\u003e \u003cp\u003e7.4 Model Assumptions 221\u003c\/p\u003e \u003cp\u003e7.5 PBPK Software 221\u003c\/p\u003e \u003cp\u003eReferences 223\u003c\/p\u003e \u003cp\u003e\u003cb\u003e8 Pbpk Modeling Of Biotherapeutics 225\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e8.1 Introduction 226\u003c\/p\u003e \u003cp\u003e8.2 Therapeutic Proteins 226\u003c\/p\u003e \u003cp\u003e8.2.1 Peptides and Proteins 226\u003c\/p\u003e \u003cp\u003e8.2.2 Antibodies and Antibody-Based Therapies 227\u003c\/p\u003e \u003cp\u003e8.3 Pharmacokinetics of Therapeutic Proteins 234\u003c\/p\u003e \u003cp\u003e8.3.1 Absorption 234\u003c\/p\u003e \u003cp\u003e8.3.2 Renal Elimination 235\u003c\/p\u003e \u003cp\u003e8.3.3 Immunogenicity 235\u003c\/p\u003e \u003cp\u003e8.3.4 PEGylation 239\u003c\/p\u003e \u003cp\u003e8.3.5 Transport by Convective and Transcytotic Extravasation 239\u003c\/p\u003e \u003cp\u003e8.3.6 Catabolic Elimination (Proteolysis) 239\u003c\/p\u003e \u003cp\u003e8.3.7 FcRn-Mediated Protection of IgGs Against Catabolism in FcRn-Rich Cells 241\u003c\/p\u003e \u003cp\u003e8.3.8 Distribution and lymphatic elimination 242\u003c\/p\u003e \u003cp\u003e8.3.9 Target-Mediated Drug Disposition and Receptor-Mediated Endocytosis 243\u003c\/p\u003e \u003cp\u003e8.4 PBPK Modeling of Monoclonal Antibodies 244\u003c\/p\u003e \u003cp\u003e8.4.1 Full PBPK Model for Monoclonal Antibodies 244\u003c\/p\u003e \u003cp\u003e8.4.2 Minimal PBPK Model for Monoclonal Antibodies 253\u003c\/p\u003e \u003cp\u003e8.5 Applications of PBPK Modeling of Monoclonal Antibodies 253\u003c\/p\u003e \u003cp\u003e8.5.1 Pharmacokinetic Scaling 253\u003c\/p\u003e \u003cp\u003e8.5.2 PBPK Integration with Pharmacodynamics of Monoclonal Antibodies 255\u003c\/p\u003e \u003cp\u003eKeywords 156\u003c\/p\u003e \u003cp\u003eReferences 258\u003c\/p\u003e \u003cp\u003e\u003cb\u003e9 Uncertainty And Population Variability 263\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e9.1 Introduction 264\u003c\/p\u003e \u003cp\u003e9.2 Distinguishing Uncertainty and Variability 264\u003c\/p\u003e \u003cp\u003e9.3 Sources of Uncertainty in Drug-related Parameters 264\u003c\/p\u003e \u003cp\u003e9.4 Sources of Variability in System Parameters 266\u003c\/p\u003e \u003cp\u003e9.5 Handling Population Variability 269\u003c\/p\u003e \u003cp\u003e9.5.1 \u003ci\u003eA POSTERIORI \u003c\/i\u003eand \u003ci\u003eA PRIORI \u003c\/i\u003eApproaches to Handling Population Variability 269\u003c\/p\u003e \u003cp\u003e9.5.2 Correlations Between Parameters 271\u003c\/p\u003e \u003cp\u003e9.6 Uncertainty and Sensitivity Analysis 272\u003c\/p\u003e \u003cp\u003e9.6.1 Local Sensitivity Analysis (One-at-a-time (OAT) and Derivative-based Methods) 272\u003c\/p\u003e \u003cp\u003e9.6.2 Parameter Interactions and Global Sensitivity Analysis (GSA) 275\u003c\/p\u003e \u003cp\u003e9.6.3 Global Sensitivity Analysis for Correlated Parameters (cGSA) 278\u003c\/p\u003e \u003cp\u003e9.6.4 Applications of Sensitivity Analysis for PBPK Models 280\u003c\/p\u003e \u003cp\u003e9.6.5 Limitations of Global Sensitivity Analysis 281\u003c\/p\u003e \u003cp\u003e9.7 Uncertainty and Population Variability in Clinical Efficacy and Safety 282\u003c\/p\u003e \u003cp\u003eKeywords 285\u003c\/p\u003e \u003cp\u003eReferences 285\u003c\/p\u003e \u003cp\u003e\u003cb\u003e10 Nonclinical, Clinical, and Model-Informed\u003c\/b\u003e \u003cb\u003eDrug Development 293\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e10.1 Introduction: An Overview of Different Phases of Drug Development 294\u003c\/p\u003e \u003cp\u003e10.2 Nonclinical Development 295\u003c\/p\u003e \u003cp\u003e10.2.1 Preclinical Pharmacology, PK\/PD Modeling, and Human Dose Prediction 297\u003c\/p\u003e \u003cp\u003e10.2.2 Safety and Toxicology Studies 297\u003c\/p\u003e \u003cp\u003e10.2.3 Studies with Radiolabeled Compound 298\u003c\/p\u003e \u003cp\u003e10.3 Clinical Pharmacology Studies 302\u003c\/p\u003e \u003cp\u003e10.3.1 First-in-Human, Single, and Multiple Ascending Dose Studies 302\u003c\/p\u003e \u003cp\u003e10.3.2 Biopharmaceutics – Absolute Oral Bioavailability and Bioequivalence Study 304\u003c\/p\u003e \u003cp\u003e10.3.3 Food Effect Study 304\u003c\/p\u003e \u003cp\u003e10.3.4 Organ (Hepatic and Renal) Impairment Study 305\u003c\/p\u003e \u003cp\u003e10.3.5 Pediatric Assessment 306\u003c\/p\u003e \u003cp\u003e10.3.6 Mass Balance Study 307\u003c\/p\u003e \u003cp\u003e10.3.7 Drug Interaction Study 307\u003c\/p\u003e \u003cp\u003e10.3.8 Pharmacogenomics Study 308\u003c\/p\u003e \u003cp\u003e10.3.9 Thorough QT (TQT) and Concentration QT (C-QT) Study 308\u003c\/p\u003e \u003cp\u003e10.3.10 Immunogenicity Assays and Comparability Study for Biologics 309\u003c\/p\u003e \u003cp\u003e10.3.11 Drug Labelling 309\u003c\/p\u003e \u003cp\u003e10.4 Clinical Development in Oncology 310\u003c\/p\u003e \u003cp\u003e10.5 Fast Track Routes to Address Unmet Medical Need in the Treatment of Serious Conditions 311\u003c\/p\u003e \u003cp\u003e10.6 Model-Informed Drug Development 312\u003c\/p\u003e \u003cp\u003e10.7 Physiologically Based Pharmacokinetic Models Complementing Clinical Pharmacology Studies 314\u003c\/p\u003e \u003cp\u003e10.8 PBPK in Oncology 315\u003c\/p\u003e \u003cp\u003eRegulatory Guidelines 316\u003c\/p\u003e \u003cp\u003eReferences 319\u003c\/p\u003e \u003cp\u003e\u003cb\u003eSection II. Applications In The Pharmaceutical\u003c\/b\u003e \u003cb\u003eIndustry 323\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e11 Overview Of Pbpk Applications 325\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e11.1 Introduction 325\u003c\/p\u003e \u003cp\u003e11.2 PBPK Applications for Internal Decisions 326\u003c\/p\u003e \u003cp\u003e11.3 PBPK Applications for Regulatory Filing 328\u003c\/p\u003e \u003cp\u003e11.4 PBPK Modeling and Simulations Along the Value Chain 332\u003c\/p\u003e \u003cp\u003eReferences 335\u003c\/p\u003e \u003cp\u003e\u003cb\u003e12 Applications Of Hypothesis Generation And Testing\u003c\/b\u003e \u003cb\u003eWith Pbpk Models 337\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e12.1 Introduction 338\u003c\/p\u003e \u003cp\u003e12.2 Hypothesis Generation and Testing with PBPK Models 338\u003c\/p\u003e \u003cp\u003e12.2.1 Parameter Estimation from Intravenous Pharmacokinetic Profiles 338\u003c\/p\u003e \u003cp\u003e12.2.2 Simulation of Oral PK Profile 341\u003c\/p\u003e \u003cp\u003e12.2.3 Sensitivity Analysis 342\u003c\/p\u003e \u003cp\u003e12.2.4 Verification of Hypotheses 346\u003c\/p\u003e \u003cp\u003e12.2.5 Auto-inhibition of Drug-Metabolizing Enzymes, Uptake and Efflux Transporters 347\u003c\/p\u003e \u003cp\u003e12.3 Hypothesis Generation and Testing Along the Value Chain 348\u003c\/p\u003e \u003cp\u003e12.4 Conclusions 351\u003c\/p\u003e \u003cp\u003eReferences 351\u003c\/p\u003e \u003cp\u003e\u003cb\u003e13 Applications of Physiologically Based Pharmacokinetic\u003c\/b\u003e \u003cb\u003eModels Integrated With Drug Effect Models (Pbpk\/Pd) 353\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e13.1 Introduction: Integration of PBPK with Drug Effect Models 354\u003c\/p\u003e \u003cp\u003e13.2 Dosing in Specific Populations 355\u003c\/p\u003e \u003cp\u003e13.3 PBPK\/PD for Bottom-Up Prediction of Inter-Patient Variability in Drug Response 357\u003c\/p\u003e \u003cp\u003e13.4 PBPK\/PD for Predicting the Inter-Patient Variability in Response to Prodrugs and Active Metabolites 358\u003c\/p\u003e \u003cp\u003e13.5 PBPK\/PD When Systemic Concentrations are not the Driver forDrug Response 359\u003c\/p\u003e \u003cp\u003e13.5.1 Pre-Systemic Drug Target 359\u003c\/p\u003e \u003cp\u003e13.5.2 Effect-Site Drug Concentration Different from Systemic Concentration 360\u003c\/p\u003e \u003cp\u003e13.6 PBPK\/PD for Monoclonal Antibodies 362\u003c\/p\u003e \u003cp\u003e13.7 PBPK Models Linked to Quantitative Systems Pharmacology and Toxicology Models 363\u003c\/p\u003e \u003cp\u003e13.7.1 PBPK–QST Models to Predict Drug-Induced Liver Injury 363\u003c\/p\u003e \u003cp\u003e13.7.2 PBPK–QST Models to Predict Drug-Induced Cardiotoxicity 367\u003c\/p\u003e \u003cp\u003e13.8 Conclusions 371\u003c\/p\u003e \u003cp\u003eReferences 371\u003c\/p\u003e \u003cp\u003e\u003cb\u003e14 Pbpk Modeling and Simulations to Evaluate Clinical\u003c\/b\u003e \u003cb\u003eDrug-Drug Interactions 375\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e14.1 Introduction 376\u003c\/p\u003e \u003cp\u003e14.2 Clinical DDI Studies and Modeling Approaches to Address Key Questions Related to Drug–Drug Interactions 376\u003c\/p\u003e \u003cp\u003e14.2.1 Dedicated Clinical DDI Studies 378\u003c\/p\u003e \u003cp\u003e14.2.2 Investigation of Phenotypic Effects for NMEs Predominantly Cleared by Polymorphic Enzyme or Transporter 379\u003c\/p\u003e \u003cp\u003e14.2.3 Prospective Nested DDI Study 380\u003c\/p\u003e \u003cp\u003e14.2.4 Cocktail DDI Study 381\u003c\/p\u003e \u003cp\u003e14.2.5 PBPK Modeling and Simulations 381\u003c\/p\u003e \u003cp\u003e14.2.6 Claims Relating to Results of DDI Studies 381\u003c\/p\u003e \u003cp\u003e14.2.7 Impact on Label 382\u003c\/p\u003e \u003cp\u003e14.3 PBPK Modeling of Different Types of Drug Interactions 382\u003c\/p\u003e \u003cp\u003e14.3.1 PBPK Modeling Strategy: New Molecular Entity as Victim of CYP-Based Drug Interactions 382\u003c\/p\u003e \u003cp\u003e14.3.2 PBPK Modeling Strategy: New Molecular Entity as Perpetrator of CYP-Based Drug Interactions 383\u003c\/p\u003e \u003cp\u003e14.3.3 Non-CYP Based Drug Interactions 384\u003c\/p\u003e \u003cp\u003e14.3.4 Transporter-Mediated Drug Interactions 385\u003c\/p\u003e \u003cp\u003e14.4 DDI Predictions with PBPK Modeling and Simulations in Clinical Drug Development and Regulatory Submissions 387\u003c\/p\u003e \u003cp\u003e14.4.1 DDI Predictions Along the Value Chain (Figure 14.5) 387\u003c\/p\u003e \u003cp\u003e14.4.2 Possible Regulatory Outcomes, Based on the Predictions from a Verified and Validated PBPK Model 389\u003c\/p\u003e \u003cp\u003e14.4.3 Regulatory Acceptance of PBPK Analyses Included in Regulatory Submissions 390\u003c\/p\u003e \u003cp\u003e14.4.4 Predictive Performance of PBPK Models 391\u003c\/p\u003e \u003cp\u003e14.5 Comparison of DDI Prediction Using Static and Dynamic Models 392\u003c\/p\u003e \u003cp\u003e14.6 Conclusions 393\u003c\/p\u003e \u003cp\u003eReferences 394\u003c\/p\u003e \u003cp\u003e\u003cb\u003e15 Dose Extrapolation Across Populations (Healthy Adult\u003c\/b\u003e \u003cb\u003eCaucasian To Pediatric, Pregnant Women, Different\u003c\/b\u003e \u003cb\u003eEthnicities, Geriatric, Smokers And Obese Populations) 397\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e15.1 Introduction 398\u003c\/p\u003e \u003cp\u003e15.2 PBPK Modeling Strategy for Dose Extrapolation to Specific Populations 398\u003c\/p\u003e \u003cp\u003e15.3 Potential Benefits of PBPK Modeling for Dose Extrapolations to Specific Populations 399\u003c\/p\u003e \u003cp\u003e15.4 Dose Extrapolations to Specific populations 404\u003c\/p\u003e \u003cp\u003e15.4.1 Pediatric Starting Dose Selection 404\u003c\/p\u003e \u003cp\u003e15.4.2 Pregnancy 406\u003c\/p\u003e \u003cp\u003e15.4.3 Ethnicity – Japanese Population 407\u003c\/p\u003e \u003cp\u003e15.4.4 Geriatric Population 408\u003c\/p\u003e \u003cp\u003e15.4.5 Obese 409\u003c\/p\u003e \u003cp\u003e15.4.6 Smokers 410\u003c\/p\u003e \u003cp\u003e15.5 Conclusions 410\u003c\/p\u003e \u003cp\u003eReferences 411\u003c\/p\u003e \u003cp\u003e\u003cb\u003e16 Dose Extrapolation Across Populations: Healthy\u003c\/b\u003e \u003cb\u003eAdult To Hepatic And Renal Impairment Populations 417\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e16.1 Introduction 418\u003c\/p\u003e \u003cp\u003e16.2 Pathophysiological Changes in Organ Impairment 419\u003c\/p\u003e \u003cp\u003e16.2.1 Hepatic Impairment 419\u003c\/p\u003e \u003cp\u003e16.2.2 Renal Impairment 420\u003c\/p\u003e \u003cp\u003e16.3 PBPK Modeling Strategy: Model Development, Verification, Validation, and Application 420\u003c\/p\u003e \u003cp\u003e16.4 Benefits of Applying Validated PBPK Models to Organ-Impaired Populations 421\u003c\/p\u003e \u003cp\u003e16.4.1 Enhancing Regulatory Confidence in the Application of PBPK Modeling for the Prediction of Exposure in the Organ-Impaired Population 421\u003c\/p\u003e \u003cp\u003e16.4.2 Contribution of PBPK to the Totality of Evidence in Evaluating the Effect of Renal Impairment on Drug Exposure to Inform Labelling 424\u003c\/p\u003e \u003cp\u003e16.5 Conclusions 425\u003c\/p\u003e \u003cp\u003eReferences 426\u003c\/p\u003e \u003cp\u003e\u003cb\u003e17 Absorption-Related Applications Of Pbpk Modeling 429\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e17.1 Introduction 429\u003c\/p\u003e \u003cp\u003e17.2 In Vitro – In Vivo Disconnect, Parameter Non-Identifiability and the Importance of Identifying Factors Limiting Absorption Through a Deconvolution of the Mechanisms Contributing to Gut Bioavailability 431\u003c\/p\u003e \u003cp\u003e17.3 Non-Regulatory Internal Applications of PBPK Modeling and Simulations 433\u003c\/p\u003e \u003cp\u003e17.3.1 Prediction of Fraction Absorbed 433\u003c\/p\u003e \u003cp\u003e17.3.2 Oral Formulation Development 433\u003c\/p\u003e \u003cp\u003e17.4 Regulatory Applications of PBPK Modeling and Simulations 438\u003c\/p\u003e \u003cp\u003e17.4.1 Food–Drug Interactions 438\u003c\/p\u003e \u003cp\u003e17.4.2 Interactions of a Poorly Soluble Weak Base with Acid Reducing Agents (ARAs) 444\u003c\/p\u003e \u003cp\u003e17.4.3 In Vitro – In Vivo Correlations (IVIVCs) to Serve as Surrogate for Bioequivalence Testing (Case Study 12) 445\u003c\/p\u003e \u003cp\u003e17.4.4 Biowaivers Based on Virtual Bioequivalence 449\u003c\/p\u003e \u003cp\u003e17.4.5 Virtual Bioequivalence of Locally Acting Products (LAPs) 450\u003c\/p\u003e \u003cp\u003e17.5 Conclusions 450\u003c\/p\u003e \u003cp\u003eReferences 452\u003c\/p\u003e \u003cp\u003e\u003cb\u003e18 Regulatory Guidelines On The Reporting Of\u003c\/b\u003e \u003cb\u003ePhysiologically Based Pharmacokinetic (Pbpk)\u003c\/b\u003e \u003cb\u003eModeling Analysis 457\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e18.1 Introduction 457\u003c\/p\u003e \u003cp\u003e18.2 Food and Drug Administration (FDA) Guidelines 458\u003c\/p\u003e \u003cp\u003e18.3 European Medicines Agency (EMA) Guidelines 459\u003c\/p\u003e \u003cp\u003e18.4 Comparison of FDA and EMA Guidelines 461\u003c\/p\u003e \u003cp\u003e18.5 Risk-Informed Evidentiary Framework to Assess PBPK Model Credibility 463\u003c\/p\u003e \u003cp\u003e18.6 Drug Model Verification of Locally Acting Products (LAPs) 464 References 466\u003c\/p\u003e \u003cp\u003e\u003cb\u003e19 Resolving The Challenges To Establishing Confidence\u003c\/b\u003e \u003cb\u003eIn Pbpk Models 469\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e19.1 Introduction 470\u003c\/p\u003e \u003cp\u003e19.2 Requirements for Developing Mechanistically Credible PBPK Models for the Three Broad Categories of Applications 470\u003c\/p\u003e \u003cp\u003e19.3 Challenges to Developing Mechanistically Credible PBPK Models and Consequences 473\u003c\/p\u003e \u003cp\u003e19.3.1 Model Building 473\u003c\/p\u003e \u003cp\u003e19.3.2 Model Verification of Predicted Exposure and Validation of Predictive Performance 476\u003c\/p\u003e \u003cp\u003e19.4 Resolving the Challenges to Developing Mechanistically Credible PBPK Models 476\u003c\/p\u003e \u003cp\u003e19.5 Totality of Evidence 478\u003c\/p\u003e \u003cp\u003e19.6 Conclusions 480\u003c\/p\u003e \u003cp\u003eReferences 481\u003c\/p\u003e \u003cp\u003e\u003cb\u003e20 Epilogue 483\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e20.1 PBPK Modeling Successes 483\u003c\/p\u003e \u003cp\u003e20.2 Challenges 484\u003c\/p\u003e \u003cp\u003e20.2.1 Drug Model Parameterization 484\u003c\/p\u003e \u003cp\u003e20.2.2 Knowledge Gaps in Physiological Parameters 485\u003c\/p\u003e \u003cp\u003e20.2.3 Prospective Validation of Prediction Performance 485\u003c\/p\u003e \u003cp\u003e20.3 Meeting the Challenges 485\u003c\/p\u003e \u003cp\u003e20.4 Future Directions for PBPK Modeling 486\u003c\/p\u003e \u003cp\u003eReferences 488\u003c\/p\u003e \u003cp\u003e\u003cb\u003eSection III. Case Studies Of Pbpk Applications In\u003c\/b\u003e \u003cb\u003eThe Pharmaceutical Industry 491\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eCase Study 1 Hypothesis Testing (Solubility) 493\u003c\/p\u003e \u003cp\u003eCase Study 2 Hypothesis Testing (Gastric Emptying) 499\u003c\/p\u003e \u003cp\u003eCase Study 3 Hypothesis Testing (Intestinal Loss) 505\u003c\/p\u003e \u003cp\u003eCase Study 4 Pbpk\/Pd 509\u003c\/p\u003e \u003cp\u003eCase Study 5 Drug–Drug Interaction (Inhibition) 515\u003c\/p\u003e \u003cp\u003eCase Study 6 Drug–Drug Interaction (Induction) 521\u003c\/p\u003e \u003cp\u003eCase Study 7 Genetic Polymorphism 527\u003c\/p\u003e \u003cp\u003eCase Study 8 Pediatric Extrapolation 535\u003c\/p\u003e \u003cp\u003eCase Study 9 Pregnancy 541\u003c\/p\u003e \u003cp\u003eCase Study 10 Hepatic Impairment 547\u003c\/p\u003e \u003cp\u003eCase Study 11 Renal Impairment 555\u003c\/p\u003e \u003cp\u003eCase Study 12 Absorption – Ivivc 561\u003c\/p\u003e \u003cp\u003eAppendices 567\u003c\/p\u003e \u003cp\u003eIndex 579\u003c\/p\u003e \u003cp\u003e\u003cb\u003eSheila Annie Peters, PhD,\u003c\/b\u003e 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.\u003c\/p\u003e  \u003cp\u003e\u003cb\u003eThe first book dedicated to the emerging field of physiologically based pharmacokinetic modeling (PBPK)\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eNow in its second edition, \u003ci\u003ePhysiologically Based Pharmacokinetic (PBPK) Modelling and  Simulations: Principles, Methods, and Applications in the Pharma Industry\u003c\/i\u003e remains the premier reference book throughout the rapidly growing PBPK user community. Using clear and concise language, author Sheila Annie Peters connects theory with practice as she explores the vast potential of PBPK modeling for improving drug discovery and development. \u003c\/p\u003e\u003cp\u003eThis fully updated new edition covers key developments in the field of PBPK modelling and simulations that have emerged in recent years. A brand-new section provides case studies in different application areas of PBPK modelling, including drug-drug interaction, genetic polymorphism, renal impairment, and pediatric extrapolation. Additional chapters address  topics such as model-informed drug development (MIDD) and expose readers to a wide range of  current applications in the field. Throughout the book, substantially revised  chapters simplify complex topics and offer a balanced view of both the opportunities and challenges of PBPK modelling. Providing timely and comprehensive coverage of one of the most exciting new areas of pharmaceutical science, this book: \u003c\/p\u003e\u003cul\u003e\n\u003cli\u003eDescribes the principles behind physiological modeling of pharmacokinetic processes, inter-individual variability, and drug interactions for small molecule drugs and biologics\u003c\/li\u003e \u003cli\u003eFeatures a wealth of new figures and case studies of the applications of PBPK modelling along the value chain in drug discovery and development\u003c\/li\u003e \u003cli\u003eReflects the latest regulatory guidelines on the reporting of PBPK modelling analysis\u003c\/li\u003e \u003cli\u003eIncludes access to a new companion website containing code, datasets, explanations of case examples in the text, and discussion of key developments in the field\u003c\/li\u003e \u003cli\u003eContains a brief overview of the field, end-of-chapter keywords for easy reference, and an extensive bibliography\u003c\/li\u003e\n\u003c\/ul\u003e \u003cp\u003e\u003ci\u003ePhysiologically Based Pharmacokinetic (PBPK) Modeling and Simulations: Principles, Methods, and Applications in the Pharmaceutical Industry, Second Edition\u003c\/i\u003e is an indispensable ­single-volume resource for beginning and intermediate practitioners across the pharmaceutical sciences in both industry and academia.\u003c\/p\u003e","brand":"Wiley","offers":[{"title":"Default Title","offer_id":47989791195365,"sku":"NP9781119497684","price":193.95,"currency_code":"USD","in_stock":false}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/1842\/7735\/files\/9781119497684.jpg?v=1761785481","url":"https:\/\/k12savings.com\/products\/physiologically-based-pharmacokinetic-pbpk-modeling-and-simulations-isbn-9781119497684","provider":"K12savings","version":"1.0","type":"link"}