Characterization and application of physiologically based pharmacokinetic models in risk assessment

Abstract

FOREWORD 1 LIST OF ACRONYMS AND ABBREVIATIONS 2 PREFACE 3 1. INTRODUCTION 8 1.1 Context 8 1.2 Objectives 9 1.3 Organization 9 2. TISSUE DOSIMETRY IN RISK ASSESSMENT 9 2.1 Concepts 9 2.2 Application and evaluation 13 2.2.1 Interspecies extrapolation 14 2.2.2 Interindividual variability 14 2.2.3 High dose to low dose extrapolation 15 2.2.4 Route-to-route extrapolation 15 2.2.5 Model evaluation 16 3. CHARACTERIZATION AND DOCUMENTATION OF PBPK MODELS 16 3.1 Introduction 16 3.2 Scope and purpose of the model 17 3.3 Model structure and biological characterization 18 3.4 Mathematical description of ADME 19 3.5 Computer implementation and verification 20 3.6 Parameter estimation and analysis 20 3.7 Model validation and evaluation 21 3.7.1 Characterizing the level of confidence in PBPK models 22 3.7.1.1 Biological basis 22 3.7.1.2 Comparison of model simulations with data 23 3.7.1.3 Reliability of dose metric predictions (model testing, uncertainty and sensitivity analyses) 24 3.7.2 Ability of PBPK models to address PK uncertainty relative to other approaches 30 3.7.2.1 Dose metric 30 3.7.2.2 Conceptual model 30 3.7.2.3 Input parameters 31 3.7.3 Purpose-specific model evaluation 31 3.7.3.1 Interspecies extrapolation 32 3.7.3.2 Interindividual variability 34 3.7.3.3 High dose to low dose extrapolation 35 3.7.3.4 Route-to-route extrapolation 36 3.8 Documentation 37 4. APPLICATION OF PBPK MODELS IN RISK ASSESSMENT 38 4.1 Choice of critical studies 38 4.2 Selection of PBPK models 39 4.3 Evaluation of dose metrics 42 4.4 Determination of human exposures 43 5. PROCESS CONSIDERATIONS 45 5.1 Expertise 45 5.2 Training 46 5.3 Communication 47 6. CONCLUDING REMARKS 49 REFERENCES 51 ANNEX 1: GLOSSARY OF TERMS 63 ANNEX 2: FREQUENTLY ASKED QUESTIONS 68 ANNEX 3: CASE-STUDY ON INTEGRATING PBPK MODELS IN A RISK ASSESSMENT OF A CHEMICAL 72