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

1 COVER

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 SECTION I: PRINCIPLES, METHODS AND BACKGROUND INFORMATION 1 A REVIEW OF PHARMACOKINETIC AND PHARMACODYNAMIC PRINCIPLES 1.1 INTRODUCTION 1.2 PHARMACOKINETIC PRINCIPLES 1.3 PHARMACOKINETIC VARIABILITY 1.4 PHARMACOKINETICS OPTIMIZATION IN DRUG DISCOVERY 1.5 PHARMACODYNAMIC PRINCIPLES KEYWORDS REFERENCES 2 A REVIEW OF DRUG–DRUG INTERACTIONS 2.1 INTRODUCTION 2.2 DRUG INTERACTIONS MEDIATED BY ENZYMES AND TRANSPORTERS AT VARIOUS SITES 2.3 FACTORS AFFECTING DDI 2.4 IN VITRO METHODS TO EVALUATE DRUG–DRUG INTERACTIONS 2.5 SOURCES OF UNCERTAINTY 2.6 THERAPEUTIC PROTEIN–DRUG INTERACTION KEYWORDS REFERENCES 3 MODELING PHARMACOKINETICS, PHARMACODYNAMICS, AND DRUG INTERACTIONS 3.1 INTRODUCTION 3.2 MODELING PHARMACOKINETICS 3.3 PHARMACOKINETICS/PHARMACODYNAMICS AND PK/EFFICACY (EXPOSURE/RESPONSE) MODELING 3.4 PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING AND ITS INTEGRATION WITH PHARMACODYNAMICS AND EFFICACY MODELS KEYWORDS REFERENCES 4 PHYSIOLOGICAL MODEL FOR ABSORPTION 4.1 INTRODUCTION 4.2 DRUG ABSORPTION AND GUT BIOAVAILABILITY 4.3 FACTORS AFFECTING DRUG ABSORPTION AND GUT BIOAVAILABILITY 4.4 IN SILICO PREDICTIONS OF PASSIVE PERMEABILITY AND SOLUBILITY 4.5 MEASUREMENT OF PERMEABILITY, SOLUBILITY, LUMINAL STABILITY, EFFLUX, INTESTINAL METABOLISM 4.6 ABSORPTION MODELING KEYWORDS REFERENCES 5 PHYSIOLOGICAL MODEL FOR DISTRIBUTION 5.1 INTRODUCTION 5.2 FACTORS AFFECTING TISSUE DISTRIBUTION OF XENOBIOTICS 5.3 IN SILICO MODELS OF TISSUE PARTITION COEFFICIENTS 5.4 MEASUREMENT OF PARAMETERS REPRESENTING THE RATE AND EXTENT OF TISSUE DISTRIBUTION 5.5 PHYSIOLOGICAL MODEL FOR DRUG DISTRIBUTION 5.6 DRUG CONCENTRATIONS AT THE SITE OF ACTION KEYWORDS REFERENCES 6 PHYSIOLOGICAL MODELS FOR DRUG METABOLISM AND EXCRETION 6.1 INTRODUCTION 6.2 FACTORS AFFECTING DRUG METABOLISM AND EXCRETION OF XENOBIOTICS 6.3 MODELS FOR HEPATOBILIARY AND RENAL EXCRETION 6.4 PHYSIOLOGICAL MODELS REFERENCES 7 GENERIC WHOLE‐BODY PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING 7.1 INTRODUCTION 7.2 STRUCTURE OF A GENERIC PHYSIOLOGICALLY‐BASED PHARMACOKINETIC (PBPK) MODEL 7.3 SOMATIC COMPARTMENTS 7.4 MODEL ASSUMPTIONS 7.5 PBPK SOFTWARE REFERENCES 8 PBPK MODELING OF BIOTHERAPEUTICS 8.1 INTRODUCTION 8.2 THERAPEUTIC PROTEINS 8.3 PHARMACOKINETICS OF THERAPEUTIC PROTEINS 8.4 PBPK MODELING OF MONOCLONAL ANTIBODIES 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 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/PDS4.1 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.