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Peters

Physiologically-Based Pharmacokinetic (PBPK) Modeling and Simulations: Principles, Methods, and Applications in the Pharmaceutical Industry

Medium: Buch
ISBN: 978-0-470-48406-7
Verlag: WILEY
Erscheinungstermin: 27.03.2012
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The only book dedicated to physiologically-based pharmacokinetic modeling in pharmaceutical science

Physiologically-based pharmacokinetic (PBPK) modeling has become increasingly widespread within the pharmaceutical industry over the last decade, but without one dedicated book that provides the information researchers need to learn these new techniques, its applications are severely limited. Describing the principles, methods, and applications of PBPK modeling as used in pharmaceutics, Physiologically-Based Pharmacokinetic (PBPK) Modeling and Simulations fills this void.

Connecting theory with practice, the book explores the incredible potential of PBPK modeling for improving drug discovery and development. Comprised of two parts, the book first provides a detailed and systematic treatment of the principles behind physiological modeling of pharmacokinetic processes, inter-individual variability, and drug interactions for small molecule drugs and biologics. The second part looks in greater detail at the powerful applications of PBPK to drug research.

Designed for a wide audience encompassing readers looking for a brief overview of the field as well as those who need more detail, the book includes a range of important learning aids. Featuring end-of-chapter keywords for easy reference-a valuable asset for general or novice readers without a PBPK background-along with an extensive bibliography for those looking for further information, Physiologically- Based Pharmacokinetic (PBPK) Modeling and Simulations is the essential single-volume text on one of the hottest topics in the pharmaceutical sciences today.

Produkteigenschaften

  • Artikelnummer: 9780470484067
  • Medium: Buch
  • ISBN: 978-0-470-48406-7
  • Verlag: WILEY
  • Erscheinungstermin: 27.03.2012
  • Sprache(n): Englisch
  • Auflage: 1. Auflage 2012
  • Produktform: Gebunden
  • Gewicht: 754 g
  • Seiten: 450
  • Format (B x H x T): 165 x 240 x 33 mm
  • Ausgabetyp: Kein, Unbekannt
  • Nachauflage: 978-1-119-49768-4

Themen

Autoren/Hrsg.

Autoren

Sheila Annie Peters, PhD, is an Associate Principal Scientist for R&I DMPK at AstraZeneca. Previously, she was Principal Scientist at Cyprotex Discovery and lectured at the National Institute of Technology (Trichy, India), University of Madras, and Pondicherry University.

Preface xvAcknowledgments xviiSECTION I. PRINCIPLES AND METHODS 11 MODELING IN THE PHARMACEUTICAL INDUSTRY 31.1 Introduction 31.2 Modeling Approaches 41.3 Steps Needed to Maximize Effective Integration of Models into R&D Workflow 71.4 Scope of the Book 8Keywords 10References 122 PHYSIOLOGICALLY-BASED MODELING 132.1 Introduction 132.2 Examples of Physiological Modeling 142.3 Need for Physiological Models in the Pharmaceutical Industry 152.4 Organs as Compartments 152.5 Bottom-Up vs. Top-Down Modeling in Pharmacokinetics 16References 163 REVIEW OF PHARMACOKINETIC PRINCIPLES 173.1 Introduction 183.2 Routes of Administration 183.3 Drug Disposition 183.3.1 Absorption 183.3.2 Plasma Protein Binding, BloodPlasma Ratio 203.3.3 Distribution, Elimination, Half-Life, and Clearance 233.3.4 Role of Transporters in ADME 293.4 Linear and Nonlinear Pharmacokinetics 343.5 Steady-State Pharmacokinetics 343.6 Dose Estimations 373.7 Successful PK Optimization in Drug Discovery 40Keywords 40References 414 PHYSIOLOGICAL MODEL FOR ABSORPTION 434.1 Introduction 444.2 Drug Absorption and Gut Bioavailability 444.2.1 Solubility and Dissolution Rate 444.2.2 Permeability: Transcelluar, Paracellular, and Carrier-Mediated Pathways 514.2.3 Barriers to Membrane Transport--Luminal Degradation, Efflux, and Gut Metabolism 534.3 Factors Affecting Drug Absorption and Gut Bioavailability 564.3.1 Physiological Factors Affecting Oral Drug Absorption and Species Differences in Physiology 564.3.2 Compound-Dependent Factors 624.3.3 Formulation-Dependent Factors 634.4 In Silico Predictions of Passive Permeability and Solubility 664.4.1 In Silico Models for Permeability 664.4.2 In Silico Models for Solubility 674.5 Measurement of Permeability, Solubility, Luminal Stability, Efflux, and Intestinal Metabolism 674.5.1 In Vitro, in Situ and in Vivo Assays for Permeability 674.5.2 Measurement of Thermodynamic or Equilibrium Solubility 724.5.3 Luminal Stability 744.5.4 Efflux 744.5.5 In Vitro Models for Estimating Extent of Gut Metabolism 764.6 Absorption Modeling 76Keywords 83References 845 PHYSIOLOGICAL MODEL FOR DISTRIBUTION 895.1 Introduction 905.2 Factors Affecting Tissue Distribution of Xenobiotics 915.2.1 Physiological Factors and Species Differences in Physiology 915.2.2 Compound-Dependent Factors 985.3 In Silico Models of Tissue Partition Coefficients 985.4 Measurement of Parameters Representing Rate and Extent of Tissue Distribution 1055.4.1 Assessment of Rate and Extent of Brain Penetration 1055.5 Physiological Model for Drug Distribution 1105.6 Drug Concentrations at Site of Action 111Keywords 114References 1156 PHYSIOLOGICAL MODELS FOR DRUG METABOLISM AND EXCRETION 1196.1 Introduction 1196.2 Factors Affecting Drug Metabolism and Excretion of Xenobiotics 1206.3 Models for Hepatobiliary Elimination and Renal Excretion 1246.3.1 In Silico Models 1246.3.2 In Vitro Models for Hepatic Metabolism 1256.3.3 In Vitro Models for Transporters 1276.4 Physiological Models 1366.4.1 Hepatobiliary Elimination of Parent Drug and Metabolites 1366.4.2 Renal Excretion 141References 1447 GENERIC WHOLE-BODY PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELING 1537.1 Introduction 1537.2 Structure of a Generic Whole Body PBPK Model 1547.3 Model Assumptions 1577.4 Commercial PBPK Software 158References 1598 VARIABILITY, UNCERTAINTY, AND SENSITIVITY ANALYSIS 1618.1 Introduction 1618.2 Need for Uncertainty Analysis 1628.3 Sources of Physiological, Anatomical, Enzymatic, and Transporter Variability 1638.4 Modeling Uncertainty and Population Variability with Monte Carlo Simulations 1698.5 Sensitivity Analysis 1728.6 Conclusions 174Keywords 174References 1759 EVALUATION OF DRUGDRUG INTERACTION RISK WITH PBPK MODELS 1839.1 Introduction 1849.2 Factors Affecting DrugDrug Interactions 1869.3 In Vitro Methods to Evaluate DrugDrug Interactions 1909.3.1 Candidate Drug as a Potential Inhibitor 1909.3.2 Candidate Drug as a Potential Victim of Inhibition 1929.4 Static Models to Evaluate DrugDrug Interactions 1939.5 PBPK Models to Evaluate DrugDrug Interactions 1959.5.1 Intrinsic Clearance of Victim (V) in the Absence of Inhibitor or Inducer 1959.5.2 Intrinsic Clearance of Victim (V) in the Presence of Inhibitor 1969.5.3 Time-Dependent Changes in the Abundance of an Enzyme Isoform Inhibited by an MBI 1979.5.4 Intrinsic Clearance of Victim (V) in the Presence of Inducer 1979.6 Comparison of PBPK Models and Static Models for the Evaluation of Drug Drug Interactions 198Keywords 201References 20210 PHYSIOLOGICALLY-BASED PHARMACOKINETICS OF BIOTHERAPEUTICS 20910.1 Introduction 21010.2 Therapeutic Proteins 210ftoc 18 January 2012; 14:19:810.2.1 Peptides and Proteins 21010.2.2 Monoclonal Antibodies 21210.3 Pharmacokinetics of Therapeutic Proteins 21410.3.1 Peptides and Proteins 21510.3.2 Monoclonal Antibodies 22410.4 PBPK/PD Modeling for Therapeutic Proteins 23010.4.1 Need for PBPK Modeling for Therapeutic Proteins 23010.4.2 PBPK Modeling for Therapeutic Proteins 23110.4.3 Pharmacokinetic Scaling 23910.4.4 Applications of PBPK Models of Therapeutic Proteins 24210.4.5 PBPK Integration with Pharmacodynamics 24410.5 Antisense Oligonucletides and RNA Interferance 24510.5.1 Antisense Oligonucletides (ASOs) 24510.5.2 Ribonucleic Acid Interference (RNAi) 24510.5.3 Pharmacokinetics of ASOs50 and Double-Stranded RNAs 24710.5.4 Design and Modifications of ASOs to Improve Target Affinity and PD: the First, Second, and Third Generation ASOs 24910.5.5 Integration of PK/PBPK and PD Modeling 253Keywords 254References 256SECTION II. APPLICATIONS IN THE PHARMACEUTICAL INDUSTRY 26111 DATA INTEGRATION AND SENSITIVITY ANALYSIS 26311.1 Introduction 26311.2 Examples of Data Integration with PBPK Modeling 26411.3 Examples of Sensitivity Analysis with PBPK Modeling 267References 27112 HYPOTHESIS GENERATION AND PHARMACOKINETIC PREDICTIONS 27312.1 Introduction 27412.2 PBPK Simulations of Pharmacokinetic Profiles for Hypothesis Generation and Testing 27412.2.1 Methodology 27412.2.2 In Vivo Solubility 27812.2.3 Delayed Gastric Emptying 28012.2.4 Regional Variation in Intestinal Loss: Gut Wall Metabolism, Intestinal Efflux, and Luminal Degradation 28212.2.5 Enterohepatic Recirculation 28412.2.6 Inhibition of Drug-Metabolizing Enzymes 28612.2.7 Inhibition of Hepatic Uptake 28612.2.8 Inhibition of Hepatobiliary Efflux 29012.3 Pharmacokinetic Predictions 29312.3.1 Human Predictions from Preclinical Data 29312.3.2 Pharmacokinetic Predictions in Clinical Development 293References 29413 INTEGRATION OF PBPK AND PHARMACODYNAMICS 29913.1 Introduction 30013.2 Pharmacodynamic Principles 30013.2.1 Pharmacological Targets and Drug Action 30013.2.2 Functional Adaptation Processes: Tolerance, Sensitization, and Rebound (Fig 13.2) 30113.3 Pharmacodynamic Modeling 30713.3.1 ConcentrationEffect, DoseResponse Curves, and Sigmoid Emax Models 30713.3.2 Mechanism-Based PD Modeling 31513.3.3 Simple Direct Effects 31513.3.4 Models Accommodating Delayed Pharmacological Response 32113.3.5 Models Accommodating Nonlinearity in Pharmacological Response with Respect to Time 33213.4 Pharmacokinetic Modeling: Compartmental PK and PBPK 33513.5 Integration of PK or PBPK with PD Modeling 33513.6 Reasons for Poor PK/PD Correlation 33913.7 Applications of PK or PBPK/PD Modeling in Drug Discovery and Development 34013.7.1 Need for a Mechanistic PBPK/PD Integration 34113.7.2 Applications of PK or PBPK/PD in Drug Discovery 34213.7.3 Applications of PK or PBPK/PD in Drug Development 36013.8 Regulatory Perspective 37013.9 Conclusions 371Keywords 372References 37614 PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELING OF POPULATIONS 38314.1 Introduction 38314.2 Population Modeling with PBPK 38414.3 Healthy to Target Patient Population: Impact of Disease on Pharmacokinetics 38614.4 Modeling Subpopulations: Impact of Age, Gender, Co-morbidities, and Genetics on Pharmacokinetics 38914.5 Personalized Medicine with PBPK/PD 392Keyword 395References 39615 PBPK MODELS ALONG THE DRUG DISCOVERY AND DEVELOPMENT VALUE CHAIN 40115.1 Summary of Applications of PBPK Models along Value Chain 40115.2 Obstacles and Future Directions for PBPK Modeling 403Keyword 405References 405Appendices 407Index 423