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Phase I and Pharmacologic Study of Oral Fluorouracil on a Chronic Daily Schedule in Combination With the Dihydropyrimidine Dehydrogenase Inactivator Eniluracil

From The Johns Hopkins Oncology Center, Baltimore, MD; University of Alabama, Birmingham, AL; and Glaxo Wellcome, Inc, Research Triangle Park, NC.

Address reprint requests to Sharyn D. Baker, PharmD, Division of Pharmacology and Experimental Therapeutics, The Johns Hopkins Cancer Research Building, 1650 Orleans St, Room 1M87, Baltimore, MD 21207; email sdbaker{at}jhmi.edu

PURPOSE: To determine the maximum-tolerated dose (MTD), toxicities, and pharmacokinetics of oral fluorouracil (5-FU) administered twice daily in combination with oral eniluracil, an inactivator of dihydropyrimidine dehydrogenase, administered for 28 days every 35 days.

PATIENTS AND METHODS: Oral 5-FU 1.35 mg/m² twice daily was administered with oral eniluracil 10 mg daily for 14 to 28 days, followed by a 1-week rest 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 increased dose of eniluracil 10 mg twice daily for 28 days. A reduced dose of 5-FU 1.0 mg/m² 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 (SD) values for terminal half-life, apparent volume of distribution, and systemic clearance of 4.5 hours (0.83 hours), 19 L/m² (3.0 L/m²), and 51 mL/min/m² (13 mL/min/m²), respectively. An average of 77% of 5-FU was excreted unchanged in urine after 28 days of treatment. The mean (range) 5-FU C_SS,min values achieved at the 1.0 mg/m² dose level were 22 ng/mL (8 to 38 ng/mL).

CONCLUSION: Chronic oral administration of 5-FU with oral eniluracil is tolerable and produces 5-FU steady-state concentrations similar to those achieved with protracted intravenous administration of 5-FU on clinically relevant dose schedules. Eniluracil provides an attractive means of administering 5-FU on protracted schedules.

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