A Combined Pharmacokinetic–Pharmacodynamic (PK–PD) Model for Tumor Growth in the Rat with UFT Administration

Abstract

A combined pharmacokinetic–pharmacodynamic model was developed to simulate the response of a rat tumor to UFT, a combination of uracil with Tegafur (FT). Tegafur is oral the prodrug of 5-fluorouracil (5-FU), an anti-cancer drug for colon cancer. A physiologically based pharmacokinetic (PBPK) model was developed and fitted to experimental data from literature. Three pharmacodynamic (PD) models were developed to describe the tumor cell growth treated with 5-FU, and a dual transit compartment model gave the best fit. This result may be due to dual mechanisms of action of 5-FU, and the dual transit compartment model is able to simulate these better than the other models. The PBPK and PD models were combined, and various dosing strategies were tested. The optimal ratio of uracil to Tegafur to maximize tumor reduction and minimize systemic toxicity was found to be consistent with previous reports. The model correctly predicted the toxic effect of low dihydropyrimidine dehydrogenase (DPD) level, consistent with clinical tests. Pharmacokinetic modulating chemotherapy (PMC), which combines continuous infusion of 5-FU and periodic administration of UFT was shown to be more effective than the same dose given by continuous infusion only. This model can guide the development of dosing strategies and patient specific 5-FU therapies.