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A Combined Pharmacokinetic-Pharmacodynamic (PK-PD) Model for Tumor Growth In Rats with Uft Administration

Jong H. Sung1, Anjali Dhiman2, and Michael L. Shuler1. (1) Chemical and Biomolecular Engineering, Cornell University, 120 Olin Hall, Ithaca, NY 14853, (2) Market Analytics, Roche pharmaceuticals, Nutley, NJ 07043

A combined pharmacokinetic-pharmacodynamic model was developed to simulate the response of a rat tumor to UFT, which is combination of uracil with Tegafur (FT). Tegafur is oral prodrug of 5-fluorouracil (5-FU), 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.