LAUSR

Background/Aim: Oral 5-fluorouracil (5-FU)-based prodrugs, used in cancer chemotherapeutic regimens, exhibit large inter- and intra-patient variability in plasma 5-FU concentrations, contributing to treatment failure. Although dosage determination criteria according to plasma drug concentrations are required, the relationship between pharmacokinetics and drug response after multiple oral 5-FU derivative administrations remain unknown. Materials and Methods: We evaluated the pharmacokinetics and pharmacodynamics/toxicodynamics of uracil-tegafur (UFT) after multiple administrations in colorectal cancer (CRC) model rats, and applied a pharmacometric approach to describe the time-course alterations of plasma 5-FU concentrations and tumor shrinkage. CRC was induced in rats using 1,2-dimethylhydrazine and dextran sulfate sodium. UFT (30 mg/kg as tegafur) was administered to CRC rats for 14 days. Results: Plasma 5-FU exposure levels increased with the dosing time, and large variations were observed in tumor 5-FU concentrations (32.0-125.8% with coefficient of variation). Although severe hematological toxicities were not observed, a weak correlation was observed between blood platelet count and the plasma 5-FU concentration (r=0.439, p=0.176). A simple pharmacokinetic-pharmacodynamic model was developed comprising of a small number of parameters and successfully describing plasma 5-FU levels and tumor shrinkage after multiple UFT administrations. Conclusion: A pharmacometric model approach can help establish the dose-determination criteria based on plasma 5-FU concentration of UFT-based regimens, and contribute to improvement of clinical outcomes.