Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations. Sheila Annie Peters

href="#ulink_dc57a010-deef-5218-ac13-779e06115f21">Figure 1.5. Entero‐hepatic recirculation of a parent drug or a metabolite.Figure 1.6. Oral pharmacokinetic profiles. (a) Maximum systemic concentratio...Figure 1.7. (a) Uptake and efflux drug transporters in intestine, liver, kid...Figure 1.8. Steady state concentrations following (a) constant rate infusion...Figure 1.9. Limiting conditions on metabolite disposition. (a) Formation‐lim...Figure 1.10. An orally administered drug or a prodrug may undergo first‐pass...Figure 1.11. Sources of variability in the physiological parameters that imp...Figure 1.12. Concentration–response curve of an agonist in (a) linear (b) lo...Figure 1.13. Concentration–response curves of a partial agonist and a full a...Figure 1.14. Target classes. (a) G‐protein‐coupled receptor (GPCR) (b) tyros...Figure 1.15. Biomarker classification (Types 0–6) and typical preclinical, c...Figure 1.16. Characteristics of an ideal biomarker. (a) A biomarker with ide...Figure 1.17. Pharmacodynamic biomarkers. (a) Types of biomarkers, assays for...

      2 Chapter 2Figure 2.1. Potential sources of DDI risks for a new molecular entity.Figure 2.2. Perpetrator and victim properties impacting drug interaction ris...

      3 Chapter 3Figure 3.1. Schematic representation of two‐compartment target‐mediated drug...Figure 3.2. Full Target‐Mediated Drug Disposition (TMDD) model with 1 compar...Figure 3.3. Linear and nonlinear phases of TMDD profiles at different doses....Figure 3.4. Population pharmacokinetic (popPK) principles. (a) Illustration ...Figure 3.5. Pharmacokinetic (PK)/pharmacodynamic (PD) models: Irreversible b...Figure 3.6. Typical PK/PD profiles for different types of PD mechanisms. (a)...Figure 3.7. Submodels describing the concentration–response curve of an agon...Figure 3.8. Receptor occupancy and drug response as a function of drug conce...Figure 3.9. Indirect response model 1. The plot in the figure has been repri...Figure 3.10 Indirect response model 2. The plot in the figure has been repri...Figure 3.11 Indirect response model 3. The activation of the β2 adrenergic r...Figure 3.12. Indirect response model 4. The plot in the figure has been repr...Figure 3.13. Static approaches to characterizing antitumor activity in precl...Figure 3.14. PK/efficacy (or exposure/response) model. The two vertical line...Figure 3.15. Cytotoxic and cytostatic dynamic mathematical models to describ...Figure 3.16. Translation of preclinical PK/efficacy model to human involves ...Figure 3.17. Translation of PK/PD/efficacy. (a) Efficacious dose is identifi...Figure 3.18. Translation of preclinical pharmacokinetic (PK)/pharmacodynamic...Figure 3.19. Impact of half‐life (t_1/2 ) on the choice of PK metric. As t Figure 3.20. Risk of assuming C_average,SS as the efficacious concentratio...Figure 3.21. Therapeutic window. (a) A once daily dosing of an oral drug sho...Figure 3.22. Types of inhibitor concentrations used as input in static equat...Figure 3.23. A comparison of inhibitor concentrations in the liver and in th...

      4 Chapter 4Figure 4.1. Gut bioavailability and intestinal loss. Gut bioavailability (F Figure 4.2. Fick's law and drug dissolution (left). Bile salts form micelles...Figure 4.3. Potential energies corresponding to different polymorphic forms....Figure 4.4. pH‐dependent solubility of an acid, base, and an ampholyte. (a) Figure 4.5. Different modes of drug transport across enterocytes. Lipophilic...Figure 4.6. Formulation choices for the different BCS classes of drugs.Figure 4.7. Determination of effective permeability with Loc‐I‐Gut.Figure 4.8. Parallel artificial membrane assay (PAMPA) experimental set up. ...Figure 4.9. Cultured cell‐line Caco‐2 in the determination of permeability....Figure 4.10. Ussing chambers in the determination of permeability.Figure 4.11. Perfused rat intestinal loop.Figure 4.12. Bidirectional Caco‐2 assay for determining efflux potential of ...Figure 4.13. Model of competing rates for the determination of gut extractio...Figure 4.14. Physiology‐based oral drug absorption model. Colonic (GU CO) an...

      5 Chapter 5Figure 5.1. Compound‐ and physiology‐dependent factors affecting rate and ex...Figure 5.2. Important transporters constituting the blood–brain barrier and ...Figure 5.3. Binding of lipophilic bases to components in lysosomal compartme...Figure 5.4. Binding of (a) moderate to strong bases to intracellular neutral...Figure 5.5. (a) Interstitial fluid is the key compartment for the pharmacolo...Figure 5.6. Brain slice uptake technique in combination with the total brain...Figure 5.7. Sub‐compartmentalization of a tissue.Figure 5.8. Scheme illustrating the determination of target tissue concentra...

      6 Chapter 6Figure 6.1. Fate of a xenobiotic. Molecules can directly undergo phase I met...Figure 6.2. Cellular processes in hepatocytes that determine the disposition...Figure 6.3. In vitro systems for metabolic stability.Figure 6.4. (a) Suspended hepatic uptake assay that relies on LC‐MS quantifi...Figure 6.5. Schematic illustration of a physiological model of hepatobiliary...Figure 6.6. Input to PBPK model from parameters generated in in vitro assays...Figure 6.7. Schematic representation of a physiological kidney model.

      7 Chapter 7Figure 7.1. Schematic illustration of a PBPK model. Blood flow rates associa...

      8 Chapter 8Figure 8.1. The complementarity‐determining regions (CDRs) are found in the ...Figure 8.2. Production of monoclonal antibodies by hybridoma technology. HGP...Figure 8.3. Bispecific antibody and antibody fragments with Fab fragments or...Figure 8.4. Strategies for antibody and antibody‐based therapeutics. CTLA4, ...Figure 8.5. Linear and non‐linear elimination mechanisms and their impact on...Figure 8.6. Risk factors contributing to anti‐drug antibody formation.Figure 8.7. Extravasation across vascular wall caused by 1. pressure gradien...Figure 8.8. FcRn protection. mAbs show a pH‐dependent affinity to FcRn with ...Figure 8.9. Receptor‐Mediated Endocytosis. Internalization and subsequent ly...Figure 8.10. Schematic representation of a generic PBPK model for macromolec...Figure 8.11. Modeling convective transport and FcRn‐dependent PK of mAbs. σ...

      9 Chapter 9Figure