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

Sharyn D. Baker, Robert B Diasio, Seamus O'Reilly, V. Sol Lucas, Soo Peang Khor, Susan E. Sartorius, Ross C. Donehower, Louise B. Grochow, Thomas Spector, John A. Hohneker, Eric K. Rowinsky

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60 Citations (Scopus)

Abstract

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. (C) 2000 American Society of Clinical Oncology.

Original languageEnglish (US)
Pages (from-to)915-926
Number of pages12
JournalJournal of Clinical Oncology
Volume18
Issue number4
StatePublished - Feb 2000
Externally publishedYes

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Dihydrouracil Dehydrogenase (NADP)
Fluorouracil
Appointments and Schedules
eniluracil
Maximum Tolerated Dose

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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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. / Baker, Sharyn D.; Diasio, Robert B; O'Reilly, Seamus; Lucas, V. Sol; Khor, Soo Peang; Sartorius, Susan E.; Donehower, Ross C.; Grochow, Louise B.; Spector, Thomas; Hohneker, John A.; Rowinsky, Eric K.

In: Journal of Clinical Oncology, Vol. 18, No. 4, 02.2000, p. 915-926.

Research output: Contribution to journalArticle

Baker, SD, Diasio, RB, O'Reilly, S, Lucas, VS, Khor, SP, Sartorius, SE, Donehower, RC, Grochow, LB, Spector, T, Hohneker, JA & Rowinsky, EK 2000, 'Phase I and pharmacologic study of oral fluorouracil on a chronic daily schedule in combination with the dihydropyrimidine dehydrogenase inactivator eniluracil', Journal of Clinical Oncology, vol. 18, no. 4, pp. 915-926.
Baker, Sharyn D. ; Diasio, Robert B ; O'Reilly, Seamus ; Lucas, V. Sol ; Khor, Soo Peang ; Sartorius, Susan E. ; Donehower, Ross C. ; Grochow, Louise B. ; Spector, Thomas ; Hohneker, John A. ; Rowinsky, Eric K. / Phase I and pharmacologic study of oral fluorouracil on a chronic daily schedule in combination with the dihydropyrimidine dehydrogenase inactivator eniluracil. In: Journal of Clinical Oncology. 2000 ; Vol. 18, No. 4. pp. 915-926.
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title = "Phase I and pharmacologic study of oral fluorouracil on a chronic daily schedule in combination with the dihydropyrimidine dehydrogenase inactivator eniluracil",
abstract = "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. (C) 2000 American Society of Clinical Oncology.",
author = "Baker, {Sharyn D.} and Diasio, {Robert B} and Seamus O'Reilly and Lucas, {V. Sol} and Khor, {Soo Peang} and Sartorius, {Susan E.} and Donehower, {Ross C.} and Grochow, {Louise B.} and Thomas Spector and Hohneker, {John A.} and Rowinsky, {Eric K.}",
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T1 - Phase I and pharmacologic study of oral fluorouracil on a chronic daily schedule in combination with the dihydropyrimidine dehydrogenase inactivator eniluracil

AU - Baker, Sharyn D.

AU - Diasio, Robert B

AU - O'Reilly, Seamus

AU - Lucas, V. Sol

AU - Khor, Soo Peang

AU - Sartorius, Susan E.

AU - Donehower, Ross C.

AU - Grochow, Louise B.

AU - Spector, Thomas

AU - Hohneker, John A.

AU - Rowinsky, Eric K.

PY - 2000/2

Y1 - 2000/2

N2 - 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. (C) 2000 American Society of Clinical Oncology.

AB - 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. (C) 2000 American Society of Clinical Oncology.

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