MODEL DEVELOPMENT, VERIFICATION, VALIDATION, AND APPLICATION
16.4 BENEFITSOFAPPLYINGVALIDATEDPBPKMODELSTOORGAN‐IMPAIRED POPULATIONS
16.5 CONCLUSIONS
REFERENCES
17 ABSORPTION‐RELATED APPLICATIONS OF PBPK MODELING
17.1 INTRODUCTION
17.2 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
17.3 NON‐REGULATORY INTERNAL APPLICATIONS OF PBPK MODELING AND SIMULATIONS
17.4 REGULATORY APPLICATIONS OF PBPK MODELING AND SIMULATIONS
17.5 CONCLUSIONS
REFERENCES
18 REGULATORY GUIDELINES ON THE REPORTING OF PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING ANALYSIS
18.1 INTRODUCTION
18.2 FOOD AND DRUG ADMINISTRATION (FDA) GUIDELINES
18.3 EUROPEAN MEDICINES AGENCY (EMA) GUIDELINES
18.4 COMPARISON OF FDA AND EMA GUIDELINES
18.5 RISK‐INFORMED EVIDENTIARY FRAMEWORK TO ASSESS PBPK MODEL CREDIBILITY
18.6 DRUG MODEL VERIFICATION OF LOCALLY ACTING PRODUCTS (LAPs)
REFERENCES
19 RESOLVING THE CHALLENGES TO ESTABLISHING CONFIDENCE IN PBPK MODELS
19.1 INTRODUCTION
19.2 REQUIREMENTS FOR DEVELOPING MECHANISTICALLY CREDIBLE PBPK MODELS FOR THE THREE BROAD CATEGORIES OF APPLICATIONS
19.3 CHALLENGES TO DEVELOPING MECHANISTICALLY CREDIBLE PBPK MODELS AND CONSEQUENCES
19.4 RESOLVING THE CHALLENGES TO DEVELOPING MECHANISTICALLY CREDIBLE PBPK MODELS
19.5 TOTALITY OF EVIDENCE
19.6 CONCLUSIONS
REFERENCES
20 EPILOGUE
20.1 PBPK MODELING SUCCESSES
20.2 CHALLENGES
20.3 MEETING THE CHALLENGES
20.4 FUTURE DIRECTIONS FOR PBPK MODELING
REFERENCES
11 SECTION III: CASE STUDIES OF PBPK APPLICATIONS IN THE PHARMACEUTICAL INDUSTRY CASE STUDY 1: HYPOTHESIS TESTING (SOLUBILITY) S1.1 IDENTIFICATION OF HIGHER IN VIVO SOLUBILITY THAN MEASURED IN VITRO REFERENCES CASE STUDY 2: HYPOTHESIS TESTING (GASTRIC EMPTYING) S2.1 IDENTIFICATION OF GASTRIC EMPTYING-LIMITED ORAL DRUG ABSORPTION REFERENCES CASE STUDY 3: HYPOTHESIS TESTING (INTESTINAL LOSS) S3.1 IDENTIFICATION OF INTESTINAL LOSS REFERENCES CASE STUDY 4: PBPK/PD S4.1 KEY QUESTION S4.2 BACKGROUND S4.3 OBJECTIVES S4.4 DATA S4.5 MODELING STRATEGY S4.6 SENSITIVITY ANALYSIS S4.7 CONCLUSION REFERENCES CASE STUDY 5: DRUG–DRUG INTERACTION (INHIBITION) S5.1 KEY QUESTION S5.2 BACKGROUND S5.3 OBJECTIVES S5.4 DATA S5.5 MODELING STRATEGY S5.6 SENSITIVITY ANALYSIS S5.7 LEARNINGS REFERENCES CASE STUDY 6: DRUG–DRUG INTERACTION (INDUCTION) S6.1 DRUG–DRUG INTERACTION RISK ASSESSMENT FOR MIDAZOLAM DUE TO CYP3A INDUCTION BY RIFAMPICIN REFERENCES CASE STUDY 7: GENETIC POLYMORPHISM S7.1 IMPACT OF GENETIC POLYMORPHISM ON THE PHARMACOKINETICS OF RISPERIDONE S7.2 Results REFERENCES CASE STUDY 8: PEDIATRIC EXTRAPOLATION S8.1 IMPACT OF UGT2B7 MATURATION ON THE PHARMACOKINETICS OF MORPHINE S8.2 CONCLUSION REFERENCES CASE STUDY 9: PREGNANCY S9.1 IMPACT OF PREGNANCY ON THE PHARMACOKINETICS OF METRONIDAZOLE S9.2 RESULTS REFERENCES CASE STUDY 10: HEPATIC IMPAIRMENT S10.1 IMPACT OF HEPATIC IMPAIRMENT ON THE PHARMACOKINETICS OF MIDAZOLAM AND LIDOCAINE S10.2 MODELING STRATEGY S10.3
