Machine generated contents note: PRINCIPLES AND METHODS -- Modeling In The Pharmaceutical Industry -- Introduction -- Modeling Approaches -- Steps Needed to Maximize Effective Integration of Models into R&D Workflow -- Scope of the Book -- Keywords -- References -- Physiologically-Based Modeling -- Introduction -- Examples of Physiological Modeling -- Need for Physiological Models in the Pharmaceutical Industry -- Organs as Compartments -- Bottom-Up vs.

Top-Down Modeling in Pharmacokinetics -- References -- Review Of Pharmacokinetic Principles -- Introduction -- Routes of Administration -- Drug Disposition -- Absorption -- Plasma Protein Binding, Blood-Plasma Ratio -- Distribution, Elimination, Half-Life, and Clearance -- Role of Transporters in ADME -- Linear and Nonlinear Pharmacokinetics -- Steady-State Pharmacokinetics -- Dose Estimations -- Successful PK Optimization in Drug Discovery -- Keywords -- References -- Physiological Model For Absorption -- Introduction -- Drug Absorption and Gut Bioavailability -- Solubility and Dissolution Rate -- Permeability: Transcelluar, Paracellular, and Carrier-Mediated Pathways -- Barriers to Membrane Transport -- Luminal Degradation, Efflux, and Gut Metabolism -- Factors Affecting Drug Absorption and Gut Bioavailability -- Physiological Factors Affecting Oral Drug Absorption and Species Differences in Physiology -- Compound-Dependent Factors -- Formulation-Dependent Factors -- In Silico Predictions of Passive Permeability and Solubility -- In Silico Models for Permeability -- In Silico Models for Solubility -- Measurement of Permeability, Solubility, Luminal Stability, Efflux, and Intestinal Metabolism -- In Vitro, in Situ and in Vivo Assays for Permeability -- Measurement of Thermodynamic or Equilibrium Solubility -- Luminal Stability -- Efflux -- In Vitro Models for Estimating Extent of Gut Metabolism -- Absorption Modeling -- Keywords -- References -- Physiological Model For Distribution -- Introduction -- Factors Affecting Tissue Distribution of Xenobiotics -- Physiological Factors and Species Differences in Physiology -- Compound-Dependent Factors -- In Silico Models of Tissue Partition Coefficients -- Measurement of Parameters Representing Rate and Extent of Tissue Distribution -- Assessment of Rate and Extent of Brain Penetration -- Physiological Model for Drug Distribution -- Drug Concentrations at Site of Action -- Keywords -- References -- Physiological Models For Drug Metabolism And Excretion -- Introduction -- Factors Affecting Drug Metabolism and Excretion of Xenobiotics -- Models for Hepatobiliary Elimination and Renal Excretion -- In Silico Models -- In Vitro Models for Hepatic Metabolism -- In Vitro Models for Transporters -- Physiological Models -- Hepatobiliary Elimination of Parent Drug and Metabolites -- Renal Excretion -- References -- Generic Whole-Body Physiologically-Based Pharmacokinetic Modeling -- Introduction -- Structure of a Generic Whole Body PBPK Model -- Model Assumptions -- Commercial PBPK Software -- References -- Variability, Uncertainty, And Sensitivity Analysis -- Introduction -- Need for Uncertainty Analysis -- Sources of Physiological, Anatomical, Enzymatic, and Transporter Variability -- Modeling Uncertainty and Population Variability with Monte Carlo Simulations -- Sensitivity Analysis -- Conclusions -- Keywords -- References -- Evaluation Of Drug-Drug Interaction Risk With Pbpk Models -- Introduction -- Factors Affecting Drug -- Drug Interactions -- In Vitro Methods to Evaluate Drug -- Drug Interactions -- Candidate Drug as a Potential Inhibitor -- Candidate Drug as a Potential Victim of Inhibition -- Static Models to Evaluate Drug -- Drug Interactions -- PBPK Models to Evaluate Drug -- Drug Interactions -- Intrinsic Clearance of Victim (V) in the Absence of Inhibitor or Inducer -- Intrinsic Clearance of Victim (V) in the Presence of Inhibitor -- Time-Dependent Changes in the Abundance of an Enzyme Isoform Inhibited by an MBI -- Intrinsic Clearance of Victim (V) in the Presence of Inducer -- Comparison of PBPK Models and Static Models for the Evaluation of Drug -- Drug Interactions -- Keywords -- References -- Physiologically-Based Pharmacokinetics Of Biotherapeutics -- Introduction -- Therapeutic Proteins -- Peptides and Proteins -- Monoclonal Antibodies -- Pharmacokinetics of Therapeutic Proteins -- Peptides and Proteins -- Monoclonal Antibodies -- PBPK/PD Modeling for Therapeutic Proteins -- Need for PBPK Modeling for Therapeutic Proteins -- PBPK Modeling for Therapeutic Proteins -- Pharmacokinetic Scaling -- Applications of PBPK Models of Therapeutic Proteins -- PBPK Integration with Pharmacodynamics -- Antisense Oligonucletides and RNA Interferance -- Antisense Oligonucletides (ASOs) -- Ribonucleic Acid Interference (RNAi) -- Pharmacokinetics of ASOs50 and Double-Stranded RNAs -- Design and Modifications of ASOs to Improve Target Affinity and PD: the First, Second, and Third Generation ASOs -- Integration of PK/PBPK and PD Modeling -- Keywords -- References -- APPLICATIONS IN THE PHARMACEUTICAL INDUSTRY -- Data Integration And Sensitivity Analysis -- Introduction -- Examples of Data Integration with PBPK Modeling -- Examples of Sensitivity Analysis with PBPK Modeling -- References -- Hypothesis Generation And Pharmacokinetic Predictions -- Introduction -- PBPK Simulations of Pharmacokinetic Profiles for Hypothesis Generation and Testing -- Methodology -- In Vivo Solubility -- Delayed Gastric Emptying -- Regional Variation in Intestinal Loss: Gut Wall Metabolism, Intestinal Efflux, and Luminal Degradation -- Enterohepatic Recirculation -- Inhibition of Drug-Metabolizing Enzymes -- Inhibition of Hepatic Uptake -- Inhibition of Hepatobiliary Efflux -- Pharmacokinetic Predictions -- Human Predictions from Preclinical Data -- Pharmacokinetic Predictions in Clinical Development -- References -- Integration Of Pbpk And Pharmacodynamics -- Introduction -- Pharmacodynamic Principles -- Pharmacological Targets and Drug Action -- Functional Adaptation Processes: Tolerance, Sensitization, and Rebound (Fig 13.2) -- Pharmacodynamic Modeling -- Concentration -- Effect, Dose -- Response Curves, and Sigmoid Emax Models -- Mechanism-Based PD Modeling -- Simple Direct Effects -- Models Accommodating Delayed Pharmacological Response -- Models Accommodating Nonlinearity in Pharmacological Response with Respect to Time -- Pharmacokinetic Modeling: Compartmental PK and PBPK -- Integration of PK or PBPK with PD Modeling -- Reasons for Poor PK/PD Correlation -- Applications of PK or PBPK/PD Modeling in Drug Discovery and Development -- Need for a Mechanistic PBPK/PD Integration -- Applications of PK or PBPK/PD in Drug Discovery -- Applications of PK or PBPK/PD in Drug Development -- Regulatory Perspective -- Conclusions -- Keywords -- References -- Physiologically-Based Pharmacokinetic Modeling Of Populations -- Introduction -- Population Modeling with PBPK -- Healthy to Target Patient Population: Impact of Disease on Pharmacokinetics -- Modeling Subpopulations: Impact of Age, Gender, Co-morbidities, and Genetics on Pharmacokinetics -- Personalized Medicine with PBPK/PD -- Keyword -- References -- PBPK Models Along The Drug Discovery And Development Value Chain

Summary of Applications of PBPK Models along Value Chain -- Obstacles and Future Directions for PBPK Modeling -- Keyword -- References.