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  • Physiologically Based Pharmacokinetic Modelling EPA Scientific Advisory Panel

    24 - 27 October 2017

    Syngenta White Paper

    1. Proof of Concept Study That Addresses the Lack of Human In Vivo Data in the Agrochemical Regulatory Environment by Employing a Population Based IVIVE-PBPK Modelling & Simulation Approach to Predict Human Internal Dosimetry

    2. Demonstration of Derivation of Data Derived Extrapolation Factors to Reduce Uncertainty in Human Health Risk Assessments

    3. Representation of the Relative Internal Dosimetry Between Consumers and the Human Equivalent Dose as Indicated by a Toxicologically Determined Point of Departure Indicating a ‘Toxicokinetic Safety Margin’

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  • Table of Contents

    Table of Contents ............................................................................................................................ 2 Abbreviations .................................................................................................................................. 5 1 PBPK Scientific Advisory Panel Syngenta Submission Documents ...................................... 7

    1.1 Syngenta White Paper .................................................................................................. 8 1.2 PBPK Modelling and Simulation Report ..................................................................... 8 1.3 Supporting Documentation – Relevant Simcyp & White Paper References ................ 8 1.4 Supporting Documentation – Simcyp Input and Output Files ..................................... 8 1.5 Supporting Documentation – In Vitro and In Vivo Study Reports ............................... 9

    2 Executive Summary ................................................................................................................. 9 3 Introduction ............................................................................................................................ 10 4 The Simcyp Population Based Simulator Platform ............................................................... 13

    4.1 General Background ................................................................................................... 13 4.2 Simcyp Version and Base PBPK Model .................................................................... 14 4.3 Building Virtual Individuals ....................................................................................... 16

    5 IVIVE-PBPK Proof of Concept Objectives........................................................................... 17 6 Acibenzolar ............................................................................................................................ 18

    6.1 Synonyms ................................................................................................................... 18 6.2 Toxicity Endpoint & Point of Departure .................................................................... 19

    Toxicity Endpoint ................................................................................................... 19 Point of Departure for Risk Assessment Purposes ................................................. 19

    6.3 Rat In Vivo Absorption, Distribution, Metabolism and Excretion ............................. 19 7 IVIVE-PBPK Modelling and Simulation Approach ............................................................. 19 8 Acibenzolar In Vitro ADME Studies (Rat & Human) ........................................................... 21

    8.1 In Vitro Investigations Carried Out ............................................................................ 21 8.2 Free Fraction in Plasma & Blood to Plasma Ratios ................................................... 21 8.3 In Vitro Metabolism.................................................................................................... 21

    9 Acibenzolar In Vivo Studies in Rat ........................................................................................ 23 9.1 In Vivo Toxicokinetic Study Design ........................................................................... 23 9.2 In Vivo Toxicokinetic Study Results .......................................................................... 24

    Intravenous Dose Toxicokinetics (1 mg/kg) ........................................................... 25 Oral Dose Toxicokinetics (1, 10 and 100 mg/kg) ................................................... 25

    10 Consumer Exposure to Acibenzolar via Food and Drinking Water ...................................... 26

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  • 11 Identification of Potentially ‘At Risk’ Populations ............................................................... 27 12 Doses for Simulation of Acute and Chronic Exposure Scenarios ......................................... 27 13 Development, Verification and Output of Rat and Human PBPK Modelling and Simulation .

    ............................................................................................................................................... 28 13.1 Rat PBPK Model ........................................................................................................ 28

    Distribution and blood binding ............................................................................... 28 Absorption............................................................................................................... 29 Elimination .............................................................................................................. 29 Rat PBPK Model Input Parameters ........................................................................ 30 Incorporating Variability into Rat PBPK Model .................................................... 31 Understanding Variability – Rat PBPK Model Sensitivity Analysis...................... 32 PBPK Model Acceptance ....................................................................................... 33 Simulation of Dietary Administration and POD Study .......................................... 34

    13.2 Human PBPK Model .................................................................................................. 37 Distribution and Blood Binding .............................................................................. 37 Absorption............................................................................................................... 38 Elimination .............................................................................................................. 38 Human PBPK Model Input Parameters .................................................................. 40 Human PBPK Model Sensitivity Analysis ............................................................. 41

    13.3 Dose Proportionality, Human Equivalent Dose Derivation and Simulation of Internal Dosimetry at the POD ................................................................................................ 42

    Dose Proportionality ............................................................................................... 42 Human Equivalent Dose ......................................................................................... 42 Simulation of Human Internal Dosimetry at the HED............................................ 43

    13.4 Simcyp Human Population Libraries and Simulation Scenarios ................................ 43 13.5 Simulations of Consumer Exposure Scenarios in Adults, Children (1 – 2 years) and

    Renally Impaired Populations .................................................................................... 44 14 Application of Population based PBPK Models to Obtain Toxicokinetic Data Derived

    Extrapolation Factors and Toxicokinetic Composite Factors ................................................ 48 14.1 Toxicokinetic Data Derived Extrapolation Factors EFAK & EFHK ............................. 48

    Selection of Dose Metric ........................................................................................ 48 Human Equivalent Dose and Animal to Human Interspecies Toxicokinetic

    Extrapolation Factor, EFAK ...................................................................................... 48 Defining Interindividual Variability in Human Populations - Intraspecies

    Toxicokinetic Extrapolation Factor, EFHK............................................................... 49 14.2 Toxicokinetic Composite Factors ............................................................................... 50

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  • 15 Composite Factors for Risk Assessment ............................................................................... 50 16 Acibenzolar Example Risk Assessment Employing Toxicokinetic DDEFs ......................... 51 17 Application of Human PBPK Model to Indicate Toxicokinetic Safety Margins .................. 52 18 Conclusion ............................................................................................................................. 54 19 References .............................................................................................................................. 55 Appendix 1: Toxicology Endpoints and Point of Departure ........................................................ 59 Appendix 2: PBPK Model Input, Output and R Script Files Provided to the SAP ...................... 61

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  • Abbreviations

    ADME Absorption, Distribution, Metabolism and Excretion ADUF Uncertainty factor for animal to human differences in toxicodynamics AKUF Uncertainty factor for animal to human differences in toxicokinetics AUC Area