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)

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

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

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

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