Effect of food on the oral bioavailability of UFT and leucovorin in cancer patients.
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.
Damle
B
B
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton and Hopewell, New Jersey 08543, USA. bharat.damle@bms.com
Ravandi
F
F
Kaul
S
S
Sonnichsen
D
D
Ferreira
I
I
Brooks
D
D
Stewart
D
D
Alberts
D
D
Pazdur
R
R
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D001682:Biological Availability; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005215:Fasting; D005260:Female; D005472:Fluorouracil / Q000097:blood; D005502:Food; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D005641:Tegafur / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D013763:Tetrahydrofolates / Q000097:blood; D013997:Time Factors; D014498:Uracil / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*
D004338:Drug Combinations; D013763:Tetrahydrofolates; C096910:UFT(R) drug; D005641:Tegafur; D014498:Uracil; D002955:Leucovorin; C005984:5-methyltetrahydrofolate; D005472:Fluorouracil