Comparative pharmacokinetic study of continuous venous infusion fluorouracil and oral fluorouracil with eniluracil in patients with advanced solid tumors

Alex Adjei, Joel M Reid, Robert B Diasio, Jeff A Sloan, Deborah A. Smith, Joseph Rubin, Henry Clement Pitot, Steven Robert Alberts, Richard M. Goldberg, Lorelei J. Hanson, Pamela Atherton, Matthew M. Ames, Charles Erlichman

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Abstract

Purpose: To compare the pharmacokinetics of continuous venous infusion (CVI) fluorouracil (5-FU) with that of oral eniluracil/5-FU and to describe toxicities and clinical activity of prolonged oral administration of eniluracil/5-FU. Patients and Methods: A randomized, open-label, cross-over study compared CVI 5-FU to an oral 5-FU/eniluracil combination. Seventeen patients (arm A) were randomly assigned to receive eniluracil/5-FU combination tablets (10:1 mg/m2 BID for 7 days) during the first study period, followed by 5-FU (300 mg/m2 CVI for 7 days) during period 2, with a 14-day washout between periods. Sixteen patients (arm B) received treatment in the opposite sequence. In period 3, all patients received eniluracil/5-FU tablets BID for 28 days. Plasma levels of 5-FU during CVI and oral administration were analyzed in periods 1 and 2. Dihydropyrimidine dehydrogenase (DPD) activity was determined by measuring plasma uracil, urinary α-fluoro-β-alanine, and peripheral-blood mononuclear cell (PBMC) DPD activity. Results: There were no grade 3 or 4 toxicities in either arm. Partial responses were observed in three patients. Another three patients had stable disease for ≥ 3 months. Eniluracil and 5-FU pharmacokinetics were similar to those observed in previous studies and were unaffected by administration sequence. The mean ± SD steady-state plasma concentration (Cp) and area under the curve (AUC)144-168h for CVI 5-FU (104 ± 45 ng/mL and 2,350 ± 826 ng·h/mL, respectively) were three-fold greater than those for oral 5-FU (38.1 ± 7.7 ng/mL and 722 ± 182 ng·h/mL, respectively [P < .00001]). Individual 5-FU concentrations during CVI were highly variable, whereas those after eniluracil/5-FU were very reproducible. DPD activity in PBMCs before each study period was normal. Conclusion: Both CVI 5-FU and oral eniluracil/5-FU were well tolerated, with moderate activity in these heavily pretreated patients. However, 5-FU steady-state Cp and AUCs achieved with oral eniluracil/5-FU were significantly less than with CVI 5-FU.

Original languageEnglish (US)
Pages (from-to)1683-1691
Number of pages9
JournalJournal of Clinical Oncology
Volume20
Issue number6
DOIs
StatePublished - Mar 15 2002

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Fluorouracil
Pharmacokinetics
Neoplasms
Dihydrouracil Dehydrogenase (NADP)
eniluracil
Tablets
Area Under Curve
Oral Administration
Uracil

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Comparative pharmacokinetic study of continuous venous infusion fluorouracil and oral fluorouracil with eniluracil in patients with advanced solid tumors. / Adjei, Alex; Reid, Joel M; Diasio, Robert B; Sloan, Jeff A; Smith, Deborah A.; Rubin, Joseph; Pitot, Henry Clement; Alberts, Steven Robert; Goldberg, Richard M.; Hanson, Lorelei J.; Atherton, Pamela; Ames, Matthew M.; Erlichman, Charles.

In: Journal of Clinical Oncology, Vol. 20, No. 6, 15.03.2002, p. 1683-1691.

Research output: Contribution to journalArticle

@article{872facea67b84569a817e1b52f635124,
title = "Comparative pharmacokinetic study of continuous venous infusion fluorouracil and oral fluorouracil with eniluracil in patients with advanced solid tumors",
abstract = "Purpose: To compare the pharmacokinetics of continuous venous infusion (CVI) fluorouracil (5-FU) with that of oral eniluracil/5-FU and to describe toxicities and clinical activity of prolonged oral administration of eniluracil/5-FU. Patients and Methods: A randomized, open-label, cross-over study compared CVI 5-FU to an oral 5-FU/eniluracil combination. Seventeen patients (arm A) were randomly assigned to receive eniluracil/5-FU combination tablets (10:1 mg/m2 BID for 7 days) during the first study period, followed by 5-FU (300 mg/m2 CVI for 7 days) during period 2, with a 14-day washout between periods. Sixteen patients (arm B) received treatment in the opposite sequence. In period 3, all patients received eniluracil/5-FU tablets BID for 28 days. Plasma levels of 5-FU during CVI and oral administration were analyzed in periods 1 and 2. Dihydropyrimidine dehydrogenase (DPD) activity was determined by measuring plasma uracil, urinary α-fluoro-β-alanine, and peripheral-blood mononuclear cell (PBMC) DPD activity. Results: There were no grade 3 or 4 toxicities in either arm. Partial responses were observed in three patients. Another three patients had stable disease for ≥ 3 months. Eniluracil and 5-FU pharmacokinetics were similar to those observed in previous studies and were unaffected by administration sequence. The mean ± SD steady-state plasma concentration (Cp) and area under the curve (AUC)144-168h for CVI 5-FU (104 ± 45 ng/mL and 2,350 ± 826 ng·h/mL, respectively) were three-fold greater than those for oral 5-FU (38.1 ± 7.7 ng/mL and 722 ± 182 ng·h/mL, respectively [P < .00001]). Individual 5-FU concentrations during CVI were highly variable, whereas those after eniluracil/5-FU were very reproducible. DPD activity in PBMCs before each study period was normal. Conclusion: Both CVI 5-FU and oral eniluracil/5-FU were well tolerated, with moderate activity in these heavily pretreated patients. However, 5-FU steady-state Cp and AUCs achieved with oral eniluracil/5-FU were significantly less than with CVI 5-FU.",
author = "Alex Adjei and Reid, {Joel M} and Diasio, {Robert B} and Sloan, {Jeff A} and Smith, {Deborah A.} and Joseph Rubin and Pitot, {Henry Clement} and Alberts, {Steven Robert} and Goldberg, {Richard M.} and Hanson, {Lorelei J.} and Pamela Atherton and Ames, {Matthew M.} and Charles Erlichman",
year = "2002",
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day = "15",
doi = "10.1200/JCO.20.6.1683",
language = "English (US)",
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pages = "1683--1691",
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issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
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T1 - Comparative pharmacokinetic study of continuous venous infusion fluorouracil and oral fluorouracil with eniluracil in patients with advanced solid tumors

AU - Adjei, Alex

AU - Reid, Joel M

AU - Diasio, Robert B

AU - Sloan, Jeff A

AU - Smith, Deborah A.

AU - Rubin, Joseph

AU - Pitot, Henry Clement

AU - Alberts, Steven Robert

AU - Goldberg, Richard M.

AU - Hanson, Lorelei J.

AU - Atherton, Pamela

AU - Ames, Matthew M.

AU - Erlichman, Charles

PY - 2002/3/15

Y1 - 2002/3/15

N2 - Purpose: To compare the pharmacokinetics of continuous venous infusion (CVI) fluorouracil (5-FU) with that of oral eniluracil/5-FU and to describe toxicities and clinical activity of prolonged oral administration of eniluracil/5-FU. Patients and Methods: A randomized, open-label, cross-over study compared CVI 5-FU to an oral 5-FU/eniluracil combination. Seventeen patients (arm A) were randomly assigned to receive eniluracil/5-FU combination tablets (10:1 mg/m2 BID for 7 days) during the first study period, followed by 5-FU (300 mg/m2 CVI for 7 days) during period 2, with a 14-day washout between periods. Sixteen patients (arm B) received treatment in the opposite sequence. In period 3, all patients received eniluracil/5-FU tablets BID for 28 days. Plasma levels of 5-FU during CVI and oral administration were analyzed in periods 1 and 2. Dihydropyrimidine dehydrogenase (DPD) activity was determined by measuring plasma uracil, urinary α-fluoro-β-alanine, and peripheral-blood mononuclear cell (PBMC) DPD activity. Results: There were no grade 3 or 4 toxicities in either arm. Partial responses were observed in three patients. Another three patients had stable disease for ≥ 3 months. Eniluracil and 5-FU pharmacokinetics were similar to those observed in previous studies and were unaffected by administration sequence. The mean ± SD steady-state plasma concentration (Cp) and area under the curve (AUC)144-168h for CVI 5-FU (104 ± 45 ng/mL and 2,350 ± 826 ng·h/mL, respectively) were three-fold greater than those for oral 5-FU (38.1 ± 7.7 ng/mL and 722 ± 182 ng·h/mL, respectively [P < .00001]). Individual 5-FU concentrations during CVI were highly variable, whereas those after eniluracil/5-FU were very reproducible. DPD activity in PBMCs before each study period was normal. Conclusion: Both CVI 5-FU and oral eniluracil/5-FU were well tolerated, with moderate activity in these heavily pretreated patients. However, 5-FU steady-state Cp and AUCs achieved with oral eniluracil/5-FU were significantly less than with CVI 5-FU.

AB - Purpose: To compare the pharmacokinetics of continuous venous infusion (CVI) fluorouracil (5-FU) with that of oral eniluracil/5-FU and to describe toxicities and clinical activity of prolonged oral administration of eniluracil/5-FU. Patients and Methods: A randomized, open-label, cross-over study compared CVI 5-FU to an oral 5-FU/eniluracil combination. Seventeen patients (arm A) were randomly assigned to receive eniluracil/5-FU combination tablets (10:1 mg/m2 BID for 7 days) during the first study period, followed by 5-FU (300 mg/m2 CVI for 7 days) during period 2, with a 14-day washout between periods. Sixteen patients (arm B) received treatment in the opposite sequence. In period 3, all patients received eniluracil/5-FU tablets BID for 28 days. Plasma levels of 5-FU during CVI and oral administration were analyzed in periods 1 and 2. Dihydropyrimidine dehydrogenase (DPD) activity was determined by measuring plasma uracil, urinary α-fluoro-β-alanine, and peripheral-blood mononuclear cell (PBMC) DPD activity. Results: There were no grade 3 or 4 toxicities in either arm. Partial responses were observed in three patients. Another three patients had stable disease for ≥ 3 months. Eniluracil and 5-FU pharmacokinetics were similar to those observed in previous studies and were unaffected by administration sequence. The mean ± SD steady-state plasma concentration (Cp) and area under the curve (AUC)144-168h for CVI 5-FU (104 ± 45 ng/mL and 2,350 ± 826 ng·h/mL, respectively) were three-fold greater than those for oral 5-FU (38.1 ± 7.7 ng/mL and 722 ± 182 ng·h/mL, respectively [P < .00001]). Individual 5-FU concentrations during CVI were highly variable, whereas those after eniluracil/5-FU were very reproducible. DPD activity in PBMCs before each study period was normal. Conclusion: Both CVI 5-FU and oral eniluracil/5-FU were well tolerated, with moderate activity in these heavily pretreated patients. However, 5-FU steady-state Cp and AUCs achieved with oral eniluracil/5-FU were significantly less than with CVI 5-FU.

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