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

Jean L. Grem, Nancy Harold, Jeremy Shapiro, Dao Qin Bi, Mary G. Quinn, Suzanne Zentko, Bruce Keith, J. Michael Hamilton, Brian P. Monahan, Sean Donavan, Frank Grollman, Geraldine Morrison, Chris H. Takimoto

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19 Scopus citations

Abstract

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 to simulate this schedule. Patients and Methods: Patients received a single 24-hour infusion of 5-FU (2,300 mg/m2 on day 2) with leucovorin (15 mg orally [PO] bid on days 1 through 3) to provide reference pharmacokinetic data. Two weeks later, patients began treatment with eniluracil (20 mg) and leucovorin (15 mg) (PO 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 seen 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 catobolite, was not detected in plasma during oral 5-FU-eniluracil therapy. DPD activity was markedly suppressed in all patients during eniluracil therapy; the inactivation persisted 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 with eniluracil and leucovorin is approximately 115-fold lower than the reference dosage for 24-hour infusional 5-FU. This difference is greater than expected 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.

Original languageEnglish (US)
Pages (from-to)3952-3963
Number of pages12
JournalJournal of Clinical Oncology
Volume18
Issue number23
DOIs
StatePublished - Dec 1 2000

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Grem, J. L., Harold, N., Shapiro, J., Bi, D. Q., Quinn, M. G., Zentko, S., Keith, B., Hamilton, J. M., Monahan, B. P., Donavan, S., Grollman, F., Morrison, G., & Takimoto, C. H. (2000). Phase I and pharmacokinetic trial of weekly oral fluorouracil given with eniluracil and low-dose leucovorin to patients with solid tumors. Journal of Clinical Oncology, 18(23), 3952-3963. https://doi.org/10.1200/JCO.2000.18.23.3952