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

9.2. Weibull distribution: effects of the shape parameter, β, the sca...Figure 9.3. Sensitivity analysis (SA) to ascribe overall uncertainty in the ...Figure 9.4. Finite difference (a) and central difference (b) methods for sen...Figure 9.5. S₁, S₂, and S₃ (S_i) are first‐order sensitivity indices. S_i is f...Figure 9.6. Impact of positive correlation of enzyme abundances on sensitivi...Figure 9.7. Sensitivity analysis to optimize model complexity. Simple models...Figure 9.8. Factors contributing to uncertainties in exposure and response. ...Figure 9.9. Factors contributing to variability in exposure and response. Fo...

      10 Chapter 10Figure 10.1. Timing of various nonclinical and clinical studies. Nonclinical...Figure 10.2. Schematic illustration of the selection of maximum recommended ...Figure 10.3. FDA pediatric study decision tree.

      11 Chapter 11Figure 11.1 Hypothesis testing with PBPK modeling to identify mechanisms und...Figure 11.2 Applications of PBPK/PD and PBPK/safety.Figure 11.3 PBPK applications related to absorption.Figure 11.4 PBPK simulations of untested scenarios.Figure 11.5 High‐impact PBPK applications for DDI predictions.Figure 11.6 PBPK simulations related to extrapolation outside study populati...Figure 11.7 Unique strengths of PBPK modeling and simulations.Figure 11.8 Applications overview along the drug discovery and development v...

      12 Chapter 12Figure 12.1 The effect of modulating CL_int,u and K_p factor on an intra...Figure 12.2 Parameter modulation needed for a compound that is likely to exp...Figure 12.3 A schematic illustration of the application of PBPK modeling for...Figure 12.4 PBPK simulations of PK profiles of compound A observed in Spragu...Figure 12.5 Two possible scenarios that can explain the reduction in EHR and...Figure 12.6 Hypothesis testing along with the drug discovery and development...

      13 Chapter 13Figure 13.1 Benefits of integrating PBPK and PD models.Figure 13.2 Applications of PBPK/PD models along the drug discovery and deve...Figure 13.3 Mechanisms of drug‐induced liver injury.Figure 13.4 Drug‐induced liver injury caused by drug inhibition of beta oxid...Figure 13.5 Drug‐induced cardiotoxicity. (a) The cardiac conduction system i...

      14 Chapter 14Figure 14.1 Timing of a dedicated drug interaction study.Figure 14.2 Decision tree leading to labeling restrictions.Figure 14.3 PBPK modeling workflow for NME as a victim of drug–drug interact...Figure 14.4 PBPK modeling workflow for NME as a perpetrator of drug–drug int...Figure 14.5 The benefits of predicting DDI using PBPK modeling and simulatio...Figure 14.6 Current gaps in the application of PBPK models for the evaluatio...Figure 14.7 Current gaps in the application of PBPK models for the evaluatio...Figure 14.8 In silico models and clinical studies to assess drug interaction...

      15 Chapter 15Figure 15.1 PBPK modeling workflow for dose extrapolation to special populat...Figure 15.2 Benefits of applying validated PBPK models to special population...Figure 15.3 FDA pediatric study decision tree.Figure 15.4 Current gaps in the application of PBPK models for dose extrapol...

      16 Chapter 16Figure 16.1 Applications of validated PBPK models for organ‐impaired populat...

      17 Chapter 17Figure 17.1 Absorption‐related applications along the drug development value...Figure 17.2 DCS classification. ¹Human jejunal permeability, usually predict...Figure 17.3 (a) Signature discrepancies between observed and simulated PK pr...Figure 17.4 (a) Absorption‐limiting steps for the different BCS/DCS classes ...Figure 17.5 PBPK modeling workflow for predicting food effect.Figure 17.6 Enhancing confidence in food effect predictions using PBPK.Figure 17.7 A PBPK model using best‐fit pharmacokinetic (PK) parameters from...Figure 17.8 Level A, Level B, and Level C In Vitro – in vivo correlations (I...Figure 17.9 Current gaps in the application of PBPK models for the predictio...

      18 Chapter 18Figure 18.1 Schematic representation of PBPK modeling workflow. Model verifi...

      19 Chapter 19Figure 19.1 Requirements to establish confidence in the PBPK models for the ...Figure 19.2 Pathway characterization.Figure 19.3 Barriers to building mechanistically credible models for the thr...Figure 19.4 Establishing confidence in PBPK model and situations in which si...Figure 19.5 Building a platform of evidence to enhance confidence in underly...

      20 Case Study 1Figure S1.1 Identifying higher in vivo solubility through hypothesis generat...

      21 Case Study 2Figure S2.1 Identifying oral drug absorption limited by gastric emptying thr...

      22 Case Study 3Figure S3.1 Identifying higher in intestinal loss through hypothesis testing...

      23 Case Study 4Figure S4.1 Modeling strategy to build a ciprofloxacin PBPK/PD model.Figure S4.2 Sensitivity analysis for process‐specific parameters and their r...

      24 Case Study 5Figure S5.1 Impact of CYP3A inhibition by itraconazole and its derivatives o...Figure S5.2 Modeling strategy for evaluating the impact of itraconazole and ...Figure S5.3 Sensitivity analysis for process‐specific parameters and their r...

      25 Case Study 6Figure S6.1 PBPK modeling is a powerful tool to explore and quantitatively p...Figure S6.2 Modeling strategy for evaluating the impact of rifampicin (DDI p...Figure S6.3 Sensitivity analysis for process‐specific parameters and their r...

      26 Case Study 7Figure S7.1 Schematic representation of different CYP2D6 genotypes and the c...Figure S7.2 Modeling strategy for extrapolation of risperidone pharmacokinet...Figure S7.3 Sensitivity analysis for process‐specific parameters and their r...Figure S7.4 Plasma concentration‐time curve profiles (mean and standard devi...

      27 Case Study 8Figure S8.1 Modeling strategy for extrapolation.Figure S8.2 Sensitivity analysis.

      28 Case Study 9Figure S9.1 Structure of the physiologically based pharmacokinetic (PBPK) mo...Figure S9.2 Modeling strategy to extrapolate pharmacokinetics of metronidazo...Figure S9.3 Metronidazole plasma concentration–time profile after intravenou...

      29 Case Study 10Figure S10.1 Modeling strategy for evaluating the impact of liver cirrhosis ...Figure S10.2 Simulation of the impact of liver cirrhosis on midazolam PK aft...Figure S10.3 Simulation of the impact of liver cirrhosis on lidocaine pharma...

      30 Case Study 11Figure S11.1 Modeling strategy for evaluating the impact of CKD (chronic kid...Figure S11.2 Simulation of the impact of CKD (chronic kidney disease) on gen...

      31 Case Study 12Figure S12.1 Schematic representation of in vitro in vivo correlation (IVIV...Figure S12.2 Sensitivity analysis plot of exposure shows that the only sign...Figure S12.3 Input and results of a virtual bioequivalence test by using a P...

      Guide

      1  COVER PAGE

      2  TITLE PAGE

      3  COPYRIGHT PAGE

      4  DEDICATION PAGE

      5  PREFACE TO THE SECOND EDITION

      6  PREFACE TO THE FIRST EDITION

      7  ACKNOWLEDGMENTS

      8  ABOUT THE COMPANION WEBSITE

      9  TABLE of Contents

      10  BEGIN READING

      11  APPENDICES

      12  INDEX

      13