1.
David E Leahy Molecular Informatics Group Newcastle University

2.
Development of PBPK Methods <ul><li>Cyprotex PLC </li></ul><ul><ul><li>HTADMET </li></ul></ul><ul><ul><li>Cloe PK (Generic PBPK) </li></ul></ul><ul><li>Generic PBPK Models for Rat & Humans </li></ul><ul><ul><li>Brightman, Leahy, Thomas & Searle, (Papers I & II) Drug Metabolism and Disposition (2004) </li></ul></ul>

3.
Physiologically Based PK Models <ul><li>Mathematical models of flow and distribution </li></ul><ul><li>Physiological parameters for specie </li></ul><ul><li>ADME Properties for compound </li></ul>

4.
In Vitro ADME <ul><li>Aqueous Solubility </li></ul><ul><li>Cell Membrane Permeability </li></ul><ul><ul><li>Caco-2, MDCK, PAMPA </li></ul></ul><ul><li>Metabolic stability </li></ul><ul><ul><li>Microsomes, hepatocytes </li></ul></ul><ul><li>Distribution </li></ul><ul><ul><li>Lipophilicity (Log D) </li></ul></ul><ul><li>HSA Binding </li></ul>

5.
AUC Predictions by PBPK

6.
Predicted Plasma Levels A, biperiden; B, acecainide; C, dofetilide; D, budesonide

7.
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

8.
Scaling(Ward Scaling) PBPK Scaling (Caudwell II) Scaling (Cauldwell I)

9.
Summary <ul><li>Generic PBPK models are valid and at least as good as inter-specie scaling from rat </li></ul><ul><li>Issues </li></ul><ul><ul><li>Different chemistry </li></ul></ul><ul><ul><ul><li>Analytical, model uncertainty </li></ul></ul></ul><ul><ul><li>Different Routes </li></ul></ul><ul><ul><li>Transparency, Provenance, Validation </li></ul></ul>