Fluorouracil is used clinically against various solid tumours. Both fluorouracil toxicity and pharmacokinetics vary highly within and between individuals. The reasons why doses are not individualised routinely are difficulties in defining, predicting and achieving an optimal fluorouracil exposure or dose because of a narrow therapeutic index, nonlinear pharmacokinetics, variabilities in administration rates and metabolism, and in targets like thymidylate synthase. To individualise fluorouracil administration before the first dose, assessment of the individual dihydropyrimidine dehydrogenase (DPD) activity may be useful, because this genetically highly polymorphic enzyme controls approximately 80% of fluorouracil elimination. A complete or partial loss of DPD activity in 0.1 and 3-5% of Caucasians, respectively, leads to increased fluorouracil exposure and toxicity. Several methods to assess DPD activity in patients have been proposed (genotyping, various phenotyping methods), but each of them has limitations, as has the fluorouracil test dose approach. To adapt exposure towards fluorouracil a priori, a combination of genotyping and phenotyping may yield better prediction of toxicity than one method alone. A prerequisite for dose adaptation is the definition of fluorouracil exposure ranges with sufficient therapeutic activity, but without serious toxicity. While an increased risk of leukopenia, diarrhoea, stomatitis, and hand-foot syndrome during continuous 5-day infusions was related to fluorouracil exposures above an area under the plasma concentration-time curve (AUC) threshold of 25-30 mg.h/L, tumour response was higher when an AUC of approximately 30 mg.h/L was achieved, illustrating the extremely narrow therapeutic window of fluorouracil. Pharmacokinetic target values are less clear for other regimens, including chronomodulated regimens, which yielded a superior clinically efficacy and tolerability in several trials. However, the monitoring of fluorouracil plasma concentrations seems principally useful for individual a posteriori dose adjustment. Whether an adaptation of the fluorouracil starting dose to the results of two DPD activity tests before fluorouracil administration a priori, and the adaptation of doses to fluorouracil exposure a posteriori is a reasonable approach to better prevent toxicity and increase efficacy, remains to be evaluated in randomised clinical studies comparing these strategies to routine clinical safety monitoring.

Purpose To describe 5-fluorouracil (5FU) pharmacokinetics, myelotoxicity and respective covariates using a simultaneous nonlinear mixed effect modelling approach. Methods Thirty patients with gastrointestinal cancer received 5FU 650 or 1000 mg/m 2 /day as 5-day continuous venous infusion (14 of whom also received cisplatin 20 mg/m 2 /day). 5FU and 5-fluoro-5,6-dihydrouracil (5FUH2) plasma concentrations were described by a pharmacokinetic model using NONMEM. Absolute leukocyte counts were described by a semimechanistic myelosuppression model. Covariate relationships were evaluated to explain the possible sources of variability in 5FU pharmacokinetics and pharmacodynamics. Results Total clearance of 5FU correlated with body surface area (BSA). Population estimate for total clearance was 249 L/h. Clearances of 5FU and 5FUH2 fractionally changed by 77%/m 2 difference from the median BSA. 5FU central and peripheral volumes of distribution were 5.56 L and 28.5 L, respectively. Estimated 5FUH2 clearance and volume of distribution were 121 L/h and 96.7 L, respectively. Baseline leukocyte count of 6.86 × 10 9 /L, as well as mean leukocyte transit time of 281 h accounting for time delay between proliferating and circulating cells, was estimated. The relationship between 5FU plasma concentrations and absolute leukocyte count was found to be linear. A higher degree of myelosuppression was attributed to combination therapy (slope = 2.82 L/mg) with cisplatin as compared to 5FU monotherapy (slope = 1.17 L/mg). Conclusions BSA should be taken into account for predicting 5FU exposure. Myelosuppression was influenced by 5FU exposure and concomitant administration of cisplatin.