Background and objective: Tegafur is an oral fluorouracil prodrug used in the treatment of colorectal cancer. The aim of this phase II, crossover, bioequivalence study was to compare the pharmacokinetics (primary objective) and tolerability (secondary objective) of tegafur-uracil (UFT) given as three daily doses (tid, reference schedule) with those obtained using a more convenient schedule of two daily doses (bid, new schedule).
Patient and methods: Twenty-one patients with metastatic colorectal cancer (median age 63 years) received the same oral daily dose of UFT (300 mg/m(2)/day) plus leucovorin (90 mg/day) divided into two or three daily doses. Patients were randomised to receive the first cycle either tid (12 patients) or bid (9 patients). The eligibility criteria included an Eastern Co-operative Oncology Group performance status of < or =1 and adequate bone-marrow, hepatic and renal function. The pharmacokinetics of uracil, fluorouracil and tegafur (high-performance liquid chromatography assays) were evaluated at steady state over 24 hours (area under the plasma concentration-time curve from 0 to 24 hours [AUC(24)], minimum plasma concentration [C(min)] and maximum plasma concentration [C(max)]). The pharmacokinetic parameters were analysed after logarithmic transformation according to a general linear model.
Results: The AUC(24)values of fluorouracil (p < 0.0001), uracil (p < 0.0001) and tegafur (p = 0.058) were greater with the bid schedule than the tid schedule. The bid : tid AUC(24) ratio (90% CI) was 1.8 (1.55, 2.10) with fluorouracil, 2.0 (1.59, 2.57) with uracil and 1.2 (1.02, 1.36) with tegafur, indicating that the bid and tid schedules were not bioequivalent. No major toxicity (grade 4) was reported, and grade 3 adverse events accounted for 9% of the total adverse events. Intra-patient comparison of the maximum toxicity grade did not demonstrate a significant difference between the bid and tid schedules (p = 0.18).
Conclusion: A 2-fold increase in the fluorouracil and uracil AUC values was observed with UFT administered bid compared with tid, without a significant impact on tolerability, suggesting that the more convenient bid schedule may improve the UFT therapeutic index.