Phase I and pharmacologic study of oral fluorouracil on a chronic daily schedule in combination with the dihydropyrimidine dehydrogenase inactivator eniluracil

Purpose: To determine the maximum-tolerated dose (MTD), toxicities, and pha rmacokinetics of oral fluorouracil (5-FU) administered twice daily in combi nation with oral eniluracil, an inactivator of dihydropyrimidine dehydrogen ase, administered for 28 days every 35 days. patients and Methods: Oral 5-FU 1.35 mg/m(2) twice daily was administered w ith oral eniluracil 10 mg daily for 14 to 28 days, followed by a I-week res t period. Eniluracil was started 1 day before 5-FU. Patients then received escalated doses of oral 5-FU 1.35 to 1.8 mg/m2 twice daily with an increase d dose of eniluracil 10 mg twice daily for 28 days. A reduced dose of 5-FU 1.0 mg/m(2) with eniluracil 20 mg twice daily was evaluated. Results: Thirty-six patients with solid malignancies were enrolled onto the study. Diarrhea was the principal dose-limiting toxicity of oral 5-FU and eniluracil given on this chronic schedule. The recommended phase II dose is 5-FU 1.0 mg/m2 twice daily with eniluracil 20 mg twice daily. Mean (80) va lues for terminal half-life, apparent volume of distribution, and systemic clearance of 4.5 hours (0.83 hours), 19 L/m(2) (3.0 L/m2), and 51 mL/min/m( 2) (13 ml/min/m(2)), respectivety, An average of 77% of 5-FU was excreted u nchanged in urine after 28 days of treatment. The mean (range) 5-FU C-SS,C- min,,,i, values achieved at the 1.0 mg/m(2) dose level were 22 ng/mL (8 to 38 ng/mL). Conclusion: Chronic oral administration of 5-FU with oral eniluracil is tol erable and produces 5-FU steady-state concentrations similar to those achie ved with protracted intravenous administration of 5-FU on clinically releva nt dose schedules. Eniluracil provides an attractive means of administering 5-FU on protracted schedules. (C) 2000 by American Society of Clinical Onc ology.