Phase I and pharmacokinetic trial of weekly oral fluorouracil given with eniluracil and low-dose leucovorin to patients with solid tumors

Purpose: Fluorouracil (5-FU) given as a weekly, high-dose 24-hour infusion is active and tolerable. We evaluated an oral regimen of eniluracil (which inactivates dihydropyrimidine dehydrogenase [DPD]), 5-FU, and leucovorin ta simulate this schedule. Patients and Methods: Patients received a single 24-hour infusion of 5-FU ( 2,300 mg/m(2) on day 2) with leucovorin(15 mg orally [PO] bid on days 1 thr ough 3) to provide reference pharmacokinetic data. Two weeks later, patient s began treatment with eniluracil (20 mg) and leucovorin (15 mg) (90 bid on days 1 through 3) and 5-FU (10 to 15 mg/m2 PO bid on day 2). Results: Dose-limiting toxicity (diarrhea, neutropenia, and fatigue) was se en with 5-FU 15 mg/m2 PO bid on day 2 given weekly for either 6 of 8 weeks or 3 of 4 weeks, whereas five of seven patients tolerated 5-FU 10 mg/m2 PO bid given weekly for 3 of 4 weeks. Eniluracil led to a 35-fold reduction in 5-FU clearance. Fluoro-beta-alanine, a 5-FU catabolite, was not detected i n plasma during oral 5-FU-eniluracil therapy. DPD activity was markedly sup pressed in all patients during eniluracil therapy; the inactivation persist ed after the last eniluracil dose; percentages of baseline values were 1.8% on day 5, 4.5% on day 12, and 23.6% on day 19. Conclusion: The recommended oral dosage of 5-FU (10 mg/m2 PO bid) given wit h eniluracil and leucovorin is approximately 115-fold lower than the refere nce dosage for 24-hour infusional 5-FU. This difference is greater than exp ected given the reduction in 5-FU clearance. DPD inactivation persisted for several weeks after completion of eniluracil therapy. (C) 2000 by American Society of Clinical Oncology.