Pharmacokinetic and demographic markers of 5-fluorouracil toxicity in 181 patients on adjuvant therapy for colorectal cancer

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BackgroundThe relationship between 5-fluorouracil (5-FU) pharmacokinetics and toxicity following i.v. bolus administration has not been extensively studied.Patients and methodsOne hundred and eighty-one patients on adjuvant therapy with 5-FU plus leucovorin for colorectal cancer were the study population. 5-FU pharmacokinetics was determined on day 2 of the first, third, and fifth cycles; type and the grade of adverse reactions were recorded on the next cycle.ResultsThe 5-FU area under the curve (AUC) measured at the first cycle ranged between 146 and 1236 mg × min/l and was significantly correlated with drug dose, patients' body weight (BW) and gender, females having higher AUCs. These covariates explained only 23% of AUC variability. AUC and age were the only covariates which discriminated between toxic (grade ≥2) and nontoxic cycles (grade <2), with an optimal AUC cut-off value of 596 mg × min/l. Such a correlation was lost during the next cycles following dose reduction because of toxicity in 80 patients.ConclusionsA method for calculating the initial 5-FU dose is proposed which takes into account patient BW, gender and a target AUC of 596 mg × min/l. Nevertheless, it appears that a substantial part of 5-FU toxicity is not linked to pharmacokinetic factors and dose adjustments must still be on the basis of careful clinical surveillance.

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