Effect of food on the oral bioavailability of UFT and leucovorin in cancer patients

B. Damle, F. Ravandi, S. Kaul, D. Sonnichsen, I. Ferreira, D. Brooks, D. Stewart, David S Alberts, R. Pazdur

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Abstract

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 × 100 mg capsules; dose in terms of FT) and leucovorin (2 × 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 ≲ 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.

Original languageEnglish (US)
Pages (from-to)517-523
Number of pages7
JournalClinical Cancer Research
Volume7
Issue number3
StatePublished - 2001

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Leucovorin
Biological Availability
Food
Area Under Curve
Neoplasms
Uracil
Fluorouracil
Tegafur
Prodrugs
Therapeutics
Cross-Over Studies
Tablets
Capsules
Meals
Colorectal Neoplasms
Pharmacokinetics
Fats
Confidence Intervals
Safety

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Damle, B., Ravandi, F., Kaul, S., Sonnichsen, D., Ferreira, I., Brooks, D., ... Pazdur, R. (2001). Effect of food on the oral bioavailability of UFT and leucovorin in cancer patients. Clinical Cancer Research, 7(3), 517-523.

Effect of food on the oral bioavailability of UFT and leucovorin in cancer patients. / Damle, B.; Ravandi, F.; Kaul, S.; Sonnichsen, D.; Ferreira, I.; Brooks, D.; Stewart, D.; Alberts, David S; Pazdur, R.

In: Clinical Cancer Research, Vol. 7, No. 3, 2001, p. 517-523.

Research output: Contribution to journalArticle

Damle, B, Ravandi, F, Kaul, S, Sonnichsen, D, Ferreira, I, Brooks, D, Stewart, D, Alberts, DS & Pazdur, R 2001, 'Effect of food on the oral bioavailability of UFT and leucovorin in cancer patients', Clinical Cancer Research, vol. 7, no. 3, pp. 517-523.
Damle B, Ravandi F, Kaul S, Sonnichsen D, Ferreira I, Brooks D et al. Effect of food on the oral bioavailability of UFT and leucovorin in cancer patients. Clinical Cancer Research. 2001;7(3):517-523.
Damle, B. ; Ravandi, F. ; Kaul, S. ; Sonnichsen, D. ; Ferreira, I. ; Brooks, D. ; Stewart, D. ; Alberts, David S ; Pazdur, R. / Effect of food on the oral bioavailability of UFT and leucovorin in cancer patients. In: Clinical Cancer Research. 2001 ; Vol. 7, No. 3. pp. 517-523.
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abstract = "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 × 100 mg capsules; dose in terms of FT) and leucovorin (2 × 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 ≲ 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.",
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AU - Ravandi, F.

AU - Kaul, S.

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AU - Stewart, D.

AU - Alberts, David S

AU - Pazdur, R.

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N2 - 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 × 100 mg capsules; dose in terms of FT) and leucovorin (2 × 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 ≲ 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.

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