Pharmacokinetic (PK) and tolerance profiles of oral tegafur/uracil (UFT) given as three versus two daily intakes

12013 Background: This phase II randomized bioequivalence cross-over study compared the tolerance and PK profiles of oral UFT (tegafur-uracil) given as 3 daily intakes (tid, usual schedule) to that obtained with 2 daily intakes (bid). Methods: Twenty-one metastatic colorectal cancer patients were enrolled (16 men, 5 women ; mean age 64, extremes 42–79 ; ECOG PS ≤ 1). Tegafur-uracil (300 mg/m2/d) and leucovorin (90 mg/d) were given for 2 consecutive four-week cycles separated by one rest week. Patients were randomized for receiving 1st cycle either tid (arm A, 12 patients) or bid (arm B, 9 patients). For each schedule, PK was evaluated at steady state, over 24 h. Plasma concentrations of tegafur, uracil and fluorouracil (FU) were analyzed by HPLC. Results: Analysis of tolerance (digestive toxicity mainly, OMS grade) showed a tendency (p = 0.08) for a greater toxicity with the bid schedule (29% grade 2, 14% grade 3) relative to tid (24% grade 2 only). Although daily doses were similar, FU and uracil AUC0–24h were respectively 1.8 and 2.0-fold higher for bid as compared to tid (95% CI were 1.5–2.1 and 1.6–2.6, respectively, p < 0.0001). For tegafur, the 1.2-fold difference was of borderline significance (p = 0.057). The greater the FU AUC0–24h, the higher the toxicity intensity (p = 0.044). Analysis of systemic exposure with respect to daily time revealed that FU (p < 0.01) and uracil (p < 0.03) AUC corresponding to the morning intake were significantly higher than those corresponding to the afternoon or evening intakes, with AUC ratio as high as 1.6 for FU and 2.9 for uracil. Such a circadian influence was not observed for tegafur. Conclusions: To reach bioequivalence, bid tegafur-uracil administration will require lower doses than those given tid. The circadian variability observed for FU and uracil PK concords with that previously reported for dihydropyrimidine deshydrogenase activity. No significant financial relationships to disclose.