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

8.5 APPLICATIONS OF PBPK MODELING OF MONOCLONAL ANTIBODIES KEYWORDS REFERENCES 9 UNCERTAINTY AND POPULATION VARIABILITY 9.1 INTRODUCTION 9.2 DISTINGUISHING UNCERTAINTY AND VARIABILITY 9.3 SOURCES OF UNCERTAINTY IN DRUG‐RELATED PARAMETERS 9.4 SOURCES OF VARIABILITY IN SYSTEM PARAMETERS 9.5 HANDLING POPULATION VARIABILITY 9.6 UNCERTAINTY AND SENSITIVITY ANALYSIS 9.7 UNCERTAINTY AND POPULATION VARIABILITY IN CLINICAL EFFICACY AND SAFETY KEYWORDS REFERENCES 10 NONCLINICAL, CLINICAL, AND MODEL‐INFORMED DRUG DEVELOPMENT 10.1 INTRODUCTION: AN OVERVIEW OF DIFFERENT PHASES OF DRUG DEVELOPMENT 10.2 NONCLINICAL DEVELOPMENT 10.3 CLINICAL PHARMACOLOGY STUDIES 10.4 CLINICAL DEVELOPMENT IN ONCOLOGY 10.5 FAST TRACK ROUTES TO ADDRESS UNMET MEDICAL NEED IN THE TREATMENT OF SERIOUS CONDITIONS 10.6 MODEL‐INFORMED DRUG DEVELOPMENT 10.7 PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS COMPLEMENTING CLINICAL PHARMACOLOGY STUDIES 10.8 PBPK IN ONCOLOGY REGULATORY GUIDELINES REFERENCES

      10  SECTION II: APPLICATIONS IN THE PHARMACEUTICAL INDUSTRY 11 OVERVIEW OF PBPK APPLICATIONS 11.1 INTRODUCTION 11.2 PBPK APPLICATIONS FOR INTERNAL DECISIONS 11.3 PBPK APPLICATIONS FOR REGULATORY FILING 11.4 PBPK MODELING AND SIMULATIONS ALONG THE VALUE CHAIN REFERENCES 12 APPLICATIONS OF HYPOTHESIS GENERATION AND TESTING WITH PBPK MODELS 12.1 INTRODUCTION 12.2 HYPOTHESIS GENERATION AND TESTING WITH PBPK MODELS 12.3 HYPOTHESIS GENERATION AND TESTING ALONG THE VALUE CHAIN 12.4 CONCLUSIONS REFERENCES 13 APPLICATIONS OF PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS INTEGRATED WITH DRUG EFFECT MODELS (PBPK/PD) 13.1 INTRODUCTION: INTEGRATION OF PBPK WITH DRUG EFFECT MODELS 13.2 DOSING IN SPECIFIC POPULATIONS 13.3 PBPK/PD FOR BOTTOM‐UP PREDICTION OF INTER‐PATIENT VARIABILITY IN DRUG RESPONSE 13.4 PBPK/PD FOR PREDICTING THE INTER‐PATIENT VARIABILITY IN RESPONSE TO PRODRUGS AND ACTIVE METABOLITES 13.5 PBPK/PDWHEN SYSTEMIC CONCENTRATIONS ARE NOTTHE DRIVER FOR DRUG RESPONSE 13.6 PBPK/PD FOR MONOCLONAL ANTIBODIES 13.7 PBPK MODELS LINKED TO QUANTITATIVE SYSTEMS PHARMACOLOGY AND TOXICOLOGY MODELS 13.8 CONCLUSIONS REFERENCES 14 PBPK MODELING AND SIMULATIONS TO EVALUATE CLINICAL DRUG‐DRUG INTERACTIONS 14.1 INTRODUCTION 14.2 CLINICAL DDI STUDIES AND MODELING APPROACHES TO ADDRESS KEY QUESTIONS RELATED TO DRUG–DRUG INTERACTIONS 14.3 PBPK MODELING OF DIFFERENT TYPES OF DRUG INTERACTIONS 14.4 DDI PREDICTIONS WITH PBPK MODELING AND SIMULATIONS INCLINICAL DRUG DEVELOPMENT AND REGULATORY SUBMISSIONS 14.5 COMPARISON OF DDI PREDICTION USING STATIC AND DYNAMIC MODELS 14.6 CONCLUSIONS REFERENCES 15 DOSE EXTRAPOLATION ACROSS POPULATIONS (HEALTHY ADULT CAUCASIAN TO PEDIATRIC, PREGNANT WOMEN, DIFFERENT ETHNICITIES, GERIATRIC, SMOKERS AND OBESE POPULATIONS) 15.1 INTRODUCTION 15.2 PBPK MODELING STRATEGY FOR DOSE EXTRAPOLATION TO SPECIFIC POPULATIONS 15.3 POTENTIAL BENEFITS OF PBPK MODELING FOR DOSE EXTRAPOLATIONS TO SPECIFIC POPULATIONS 15.4 DOSE EXTRAPOLATIONS TO SPECIFIC POPULATIONS 15.5 CONCLUSIONS REFERENCES 16 DOSE EXTRAPOLATION ACROSS POPULATIONS: HEALTHY ADULT TO HEPATIC AND RENAL IMPAIRMENT POPULATIONS 16.1 INTRODUCTION 16.2 PATHOPHYSIOLOGICAL CHANGES IN ORGAN IMPAIRMENT 16.3 PBPK MODELING STRATEGY: MODEL DEVELOPMENT, VERIFICATION, VALIDATION, AND APPLICATION 16.4 BENEFITSOFAPPLYINGVALIDATEDPBPKMODELSTOORGAN‐IMPAIRED POPULATIONS