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

The purpose of the study was to examine inter- and intrapatient variation i n 5-fluorouracil (5-FU) plasma concentrations in adult cancer patients rece iving a 3-day drug infusion. Fourteen patients received 1266 mg/m(2) N-(pho sphonacetyl)-L-aspartate (PALA) infused i,v, over 15 min on day 1, followed immediately by a loading dose of 500 mg/m(2) calcium leucovorin over 30 mi n. Then a prolonged infusion of leucovorin at 500 mg/m(2)/day and 5-FU at 1 750 mg/m(2)/day was administered as either a constant rate or as a circadia n infusion over 72 h, During constant rate infusions, 5-FU concentrations w ithin individuals varied by 1.7-fold, but no uniform time of peak or trough concentration was observed, Transformation of these data by setting the ti me 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 hig h; the times of peak 5-FU concentration occurred at the same approximate sa mpling time 43% of the time, and troughs coincided 17% of the time. No diff erence in clinical toxicity was observed when matched constant rate and cir cadian infusions of 5-FU were compared, High inter- and intrapatient variab ility exists in 5-FU plasma concentrations in adult cancer patients during constant rate infusions with no evidence of a consistent circadian rhythm i n untransformed data.