Damle B, Ravandi F, Kaul S, Sonnichsen D, Ferreira I, Brooks D, Stewart D, Alberts D, Pazdur R
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton and Hopewell, New Jersey 08543, USA.
Clin Cancer Res. 2001 Mar;7(3):517-23.
UFT is composed of tegafur (FT), a prodrug of 5-fluorouracil (5-FU), and uracil in a fixed combination (1:4). In conjunction with leucovorin, UFT is being developed for the first-line oral treatment of metastatic colorectal cancer. The effect of food on the oral bioavailability of UFT (2 x 100 mg capsules; dose in terms of FT) and leucovorin (2 x 15 mg tablets) was evaluated in a single-dose, randomized, two-way crossover study. Patients (n = 25) were assigned to receive both drugs after an overnight fast or 5 min after completion of a high-fat meal (721 calories) with a 3-day washout period between treatments; then they were permitted to continue on oral UFT/leucovorin therapy for safety assessment. UFT (300 mg/m2/day as three divided doses) and leucovorin (90 mg/day as three divided doses) were given for 28 days. After a 7-day rest, the 28-day cycle was repeated. Pharmacokinetics (n = 22 patients) were determined for FT, 5-FU, uracil, leucovorin, and 5-methyltetrahydrofolate (an active metabolite of leucovorin). The absence of food-effect on peak plasma concentration (CMAX) and the area under the curve (AUC) was concluded if the 90% confidence interval for the ratio of the treatment means was entirely contained in 0.75-1.33. Administration of UFT with food resulted in a 34% decrease in CMAX of FT, whereas the AUC of FT remained unchanged. Food decreased the CMAX and AUC values of uracil and 5-FU by 37-76%. On the contrary, the CMAX and AUC values of leucovorin and 5-methyltetrahydrofolate were increased by 14-60% with food. Time to reach CMAX for all analytes was significantly (P < or = 0.001) delayed by food. Except for the AUCs of FT, the statistical criterion for concluding a lack of food-effect was not met. These data suggest that UFT/leucovorin should not be dosed simultaneously with food. It is recommended that food should not be consumed for 1 h before and after an oral dose of UFT and leucovorin in a manner similar to pivotal Phase III trials. The 28-day oral regimen of UFT and leucovorin was generally well tolerated in the population studied.
优福定（UFT）由替加氟（FT）（5-氟尿嘧啶（5-FU）的前体药物）和尿嘧啶按固定比例（1:4）组成。与亚叶酸联合使用时，优福定正被开发用于转移性结直肠癌的一线口服治疗。在一项单剂量、随机、双向交叉研究中，评估了食物对优福定（2×100mg胶囊；以FT计的剂量）和亚叶酸（2×15mg片剂）口服生物利用度的影响。患者（n = 25）被分配在过夜禁食后或高脂餐（721卡路里）结束后5分钟接受这两种药物，两次治疗之间有3天的洗脱期；然后允许他们继续口服优福定/亚叶酸进行安全性评估。优福定（300mg/m²/天，分三次给药）和亚叶酸（90mg/天，分三次给药）给药28天。休息7天后，重复28天的周期。测定了22例患者的替加氟、5-氟尿嘧啶、尿嘧啶、亚叶酸和5-甲基四氢叶酸（亚叶酸的活性代谢产物）的药代动力学。如果治疗均值比的90%置信区间完全包含在0.75 - 1.33内，则得出食物对血浆峰浓度（CMAX）和曲线下面积（AUC）无影响的结论。与食物一起服用优福定导致替加氟的CMAX降低34%，而替加氟的AUC保持不变。食物使尿嘧啶和5-氟尿嘧啶的CMAX和AUC值降低37 - 76%。相反，食物使亚叶酸和5-甲基四氢叶酸的CMAX和AUC值增加14 - 60%。食物显著（P≤0.001）延迟了所有分析物达到CMAX的时间。除了替加氟的AUC外，未满足得出无食物影响结论的统计标准。这些数据表明优福定/亚叶酸不应与食物同时给药。建议在口服优福定和亚叶酸前后1小时内不要进食，方式与关键的III期试验相似。在所研究的人群中，优福定和亚叶酸28天的口服方案总体耐受性良好。
