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High Inter- and Intrapatient Variation in 5-Fluorouracil Plasma Concentrations during a Prolonged Drug Infusion

Developmental Therapeutics Department, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, Maryland 20889 [C. H. T., L. K. Y., B. S., F. G., C. C., J. M. H., A. P. C., C. J. A., J. L. G.], and Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland 20892 [D. J. V.]

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/m²N-(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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