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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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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Leucovorin
Fluorouracil
Pharmacokinetics
Neoplasms
Dihydrouracil Dehydrogenase (NADP)
eniluracil
beta-Alanine
Therapeutics
Neutropenia
Fatigue
Diarrhea
Appointments and Schedules

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Phase I and pharmacokinetic trial of weekly oral fluorouracil given with eniluracil and low-dose leucovorin to patients with solid tumors. / Grem, Jean L.; Harold, Nancy; Shapiro, Jeremy; Bi, Dao Qin; Quinn, Mary G.; Zentko, Suzanne; Keith, Bruce; Hamilton, J. Michael; Monahan, Brian P.; Donavan, Sean; Grollman, Frank; Morrison, Geraldine; Takimoto, Chris H.

In: Journal of Clinical Oncology, Vol. 18, No. 23, 01.12.2000, p. 3952-3963.

Research output: Contribution to journalArticle

Grem, JL, Harold, N, Shapiro, J, Bi, DQ, Quinn, MG, Zentko, S, Keith, B, Hamilton, JM, Monahan, BP, Donavan, S, Grollman, F, Morrison, G & Takimoto, CH 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, vol. 18, no. 23, pp. 3952-3963. https://doi.org/10.1200/JCO.2000.18.23.3952
Grem, Jean L. ; Harold, Nancy ; Shapiro, Jeremy ; Bi, Dao Qin ; Quinn, Mary G. ; Zentko, Suzanne ; Keith, Bruce ; Hamilton, J. Michael ; Monahan, Brian P. ; Donavan, Sean ; Grollman, Frank ; Morrison, Geraldine ; Takimoto, Chris H. / Phase I and pharmacokinetic trial of weekly oral fluorouracil given with eniluracil and low-dose leucovorin to patients with solid tumors. In: Journal of Clinical Oncology. 2000 ; Vol. 18, No. 23. pp. 3952-3963.
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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.",
author = "Grem, {Jean L.} and Nancy Harold and Jeremy Shapiro and Bi, {Dao Qin} and Quinn, {Mary G.} and Suzanne Zentko and Bruce Keith and Hamilton, {J. Michael} and Monahan, {Brian P.} and Sean Donavan and Frank Grollman and Geraldine Morrison and Takimoto, {Chris H.}",
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T1 - Phase I and pharmacokinetic trial of weekly oral fluorouracil given with eniluracil and low-dose leucovorin to patients with solid tumors

AU - Grem, Jean L.

AU - Harold, Nancy

AU - Shapiro, Jeremy

AU - Bi, Dao Qin

AU - Quinn, Mary G.

AU - Zentko, Suzanne

AU - Keith, Bruce

AU - Hamilton, J. Michael

AU - Monahan, Brian P.

AU - Donavan, Sean

AU - Grollman, Frank

AU - Morrison, Geraldine

AU - Takimoto, Chris H.

PY - 2000/12/1

Y1 - 2000/12/1

N2 - 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.

AB - 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.

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