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PBPK simulation as an alternative to animal testing
 

PBPK simulation as an alternative to animal testing

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Presentation at Animal Alternatives conference on physiologically based simulation models for reduction of animal testing

Presentation at Animal Alternatives conference on physiologically based simulation models for reduction of animal testing

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    PBPK simulation as an alternative to animal testing PBPK simulation as an alternative to animal testing Presentation Transcript

    • David E Leahy Molecular Informatics Group Newcastle University
    • Development of PBPK Methods
      • Cyprotex PLC
        • HTADMET
        • Cloe PK (Generic PBPK)
      • Generic PBPK Models for Rat & Humans
        • Brightman, Leahy, Thomas & Searle, (Papers I & II) Drug Metabolism and Disposition (2004)
    • Physiologically Based PK Models
      • Mathematical models of flow and distribution
      • Physiological parameters for specie
      • ADME Properties for compound
    • In Vitro ADME
      • Aqueous Solubility
      • Cell Membrane Permeability
        • Caco-2, MDCK, PAMPA
      • Metabolic stability
        • Microsomes, hepatocytes
      • Distribution
        • Lipophilicity (Log D)
      • HSA Binding
    • AUC Predictions by PBPK
    • Predicted Plasma Levels A, biperiden; B, acecainide; C, dofetilide; D, budesonide
    • PBPK versus Scaling Training Set Caldwell (n=176) I Ward (n=97) PBPK (n=69) Method I Method II Av. Fold E. 2.16 2.22 2.64 2.48 FE < 2 56% 52% 49% 46% FE < 3 77% 79% 70% 72% FE < 4 88% 86% 79% 75% Test Set Caldwell (n=18) Ward (n=18) PBPK (n=18) Method I Method II Av. Fold E. 2.61 2.53 3.44 2.80 FE < 2 50% 50% 28% 50% FE < 3 56% 56% 44% 61% FE < 4 72% 67% 61% 72% Median P/A 1.74 1.60 2.54 1.11
    • Scaling(Ward Scaling) PBPK Scaling (Caudwell II) Scaling (Cauldwell I)
    • Summary
      • Generic PBPK models are valid and at least as good as inter-specie scaling from rat
      • Issues
        • Different chemistry
          • Analytical, model uncertainty
        • Different Routes
        • Transparency, Provenance, Validation