Preclinical In Vitro Pharmacokinetic And Pharmacodynamic Models For The Hypoxia-activated Prodrug SN30000

Abstract

on the receiver compartment. This was confirmed to be as a result of bioreductive metabolism by LC-MS with high concentrations of metabolites accumulating in the diffusion chamber. This indicates that cytotoxicity may be greatly compromised in tumours or tumour regions expressing high levels of reductase and hypoxia simultaneously. This project has confirmed that SN30000 efficiently penetrates both oxic and hypoxic tumour tissue. However extremely rapid bioreductive metabolism can compromise penetration and may be an issue in some tumour types expressing high levels of reductases. This points to the need for more information of the expression of reductases in human tumours. The results of this project are part of the development of an advance SR-PK/PD model for the transport and activity of SN30000 in tumours and with the input of measured plasma PK could potentially be used to estimate expected tumour activity and to inform the optimal dosing regimen.