High inter- and intrapatient variation in 5-fluorouracil plasma concentrations during a prolonged drug infusion

Chris H. Takimoto, Lorrin K. Yee, David J. Venzon, Barbara Schuler, Frank Grollman, Chetin Chabuk, J. Michael Hamilton, Alice P. Chen, Carmen J. Allegra, Jean L. Grem

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Abstract

The purpose of the study was to examine inter- and intrapatient variation in 5-fluorouracil (5-FU) plasma concentrations in adult cancer patients receiving a 3-day drug infusion. Fourteen patients received 1266 mg/m2 N-(phosphonacetyl)-L-aspartate (PALA) infused i.v. over 15 min on day 1, followed immediately by a loading dose of 500 mg/m2 calcium leucovorin over 30 min. Then a prolonged infusion of leucovorin at 500 mg/m2/day and 5- FU at 1750 mg/m2/day was administered as either a constant rate or as a circadian infusion over 72 h. During constant rate infusions, 5-FU concentrations within individuals varied by 1.7-fold, but no uniform time of peak or trough concentration was observed. Transformation of these data by setting the time of peak to 0 h and by expressing concentrations as the percentage of the 24-h mean value revealed a nonrandom distribution of the time from peak to trough with a median time of 12 h (P = 0.027). These transformed data were also successfully fit to a circadian cosinor function (P < 0.001). During multiple constant rate 5-FU infusions, the intrapatient variability was high; the times of peak 5-FU concentration occurred at the same approximate sampling time 43% of the time, and troughs coincided 17% of the time. No difference in clinical toxicity was observed when matched constant rate and circadian infusions of 5-FU were compared. High inter- and intrapatient variability exists in 5-FU plasma concentrations in adult cancer patients during constant rate infusions with no evidence of a consistent circadian rhythm in untransformed data.

Original languageEnglish (US)
Pages (from-to)1347-1352
Number of pages6
JournalClinical Cancer Research
Volume5
Issue number6
StatePublished - Jun 1 1999

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Fluorouracil
Pharmaceutical Preparations
Leucovorin
NSC 224131
Circadian Rhythm
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Takimoto, C. H., Yee, L. K., Venzon, D. J., Schuler, B., Grollman, F., Chabuk, C., ... Grem, J. L. (1999). High inter- and intrapatient variation in 5-fluorouracil plasma concentrations during a prolonged drug infusion. Clinical Cancer Research, 5(6), 1347-1352.

High inter- and intrapatient variation in 5-fluorouracil plasma concentrations during a prolonged drug infusion. / Takimoto, Chris H.; Yee, Lorrin K.; Venzon, David J.; Schuler, Barbara; Grollman, Frank; Chabuk, Chetin; Hamilton, J. Michael; Chen, Alice P.; Allegra, Carmen J.; Grem, Jean L.

In: Clinical Cancer Research, Vol. 5, No. 6, 01.06.1999, p. 1347-1352.

Research output: Contribution to journalArticle

Takimoto, CH, Yee, LK, Venzon, DJ, Schuler, B, Grollman, F, Chabuk, C, Hamilton, JM, Chen, AP, Allegra, CJ & Grem, JL 1999, 'High inter- and intrapatient variation in 5-fluorouracil plasma concentrations during a prolonged drug infusion', Clinical Cancer Research, vol. 5, no. 6, pp. 1347-1352.
Takimoto CH, Yee LK, Venzon DJ, Schuler B, Grollman F, Chabuk C et al. High inter- and intrapatient variation in 5-fluorouracil plasma concentrations during a prolonged drug infusion. Clinical Cancer Research. 1999 Jun 1;5(6):1347-1352.
Takimoto, Chris H. ; Yee, Lorrin K. ; Venzon, David J. ; Schuler, Barbara ; Grollman, Frank ; Chabuk, Chetin ; Hamilton, J. Michael ; Chen, Alice P. ; Allegra, Carmen J. ; Grem, Jean L. / High inter- and intrapatient variation in 5-fluorouracil plasma concentrations during a prolonged drug infusion. In: Clinical Cancer Research. 1999 ; Vol. 5, No. 6. pp. 1347-1352.
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abstract = "The purpose of the study was to examine inter- and intrapatient variation in 5-fluorouracil (5-FU) plasma concentrations in adult cancer patients receiving a 3-day drug infusion. Fourteen patients received 1266 mg/m2 N-(phosphonacetyl)-L-aspartate (PALA) infused i.v. over 15 min on day 1, followed immediately by a loading dose of 500 mg/m2 calcium leucovorin over 30 min. Then a prolonged infusion of leucovorin at 500 mg/m2/day and 5- FU at 1750 mg/m2/day was administered as either a constant rate or as a circadian infusion over 72 h. During constant rate infusions, 5-FU concentrations within individuals varied by 1.7-fold, but no uniform time of peak or trough concentration was observed. Transformation of these data by setting the time of peak to 0 h and by expressing concentrations as the percentage of the 24-h mean value revealed a nonrandom distribution of the time from peak to trough with a median time of 12 h (P = 0.027). These transformed data were also successfully fit to a circadian cosinor function (P < 0.001). During multiple constant rate 5-FU infusions, the intrapatient variability was high; the times of peak 5-FU concentration occurred at the same approximate sampling time 43{\%} of the time, and troughs coincided 17{\%} of the time. No difference in clinical toxicity was observed when matched constant rate and circadian infusions of 5-FU were compared. High inter- and intrapatient variability exists in 5-FU plasma concentrations in adult cancer patients during constant rate infusions with no evidence of a consistent circadian rhythm in untransformed data.",
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AU - Grollman, Frank

AU - Chabuk, Chetin

AU - Hamilton, J. Michael

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AU - Grem, Jean L.

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