A Pilot Study to Identify Sources of Variability in 5-Fluorouracil Pharmacokinetics and Toxicity

Abstract

The aims of this study were to characterise pharmacokinetics of 5-FU and its main metabolite (5-FUH2) and to quantify factors of influence on pharmacokinetics as well as to identify factors influencing adverse events and blood cell count changes.<br /> Thirty patients (5 females, 25 males) with colorectal or oesophageal cancer receiving 5-FU 650 or 1000 mg/m²/day as 5-day continuous infusion were entered in this study. A HPLC method was used for the simultaneous assay of 5-FU and 5-FUH₂ in plasma samples obtained at baseline and at multiple time points during infusion and after the end of infusion. DPD phenotype was assessed as the UH₂/U urinary concentration ratio using LC-MS/MS. Genotying assays were developed for <i>DPYD</i> gene (23 exons), the 5' promoter region of <i>TYMS</i> gene and the <i>MTHFR</i> gene in position 677. Population pharmacokinetics of 5-FU and 5-FUH₂ were tested with NONMEM using 199 and 251 quantifiable plasma concentrations of 5-FU and 5-FUH₂, respectively. Patients’ covariables were included in the modelling process after the best basic model had been identified. <br /> An open two-compartment model with first-order elimination was found to best describe 5-FU concentration-time data, and a one-compartment model was suitable for 5-FUH₂ data. The data showed that total clearance of 5-FU tends to increase with body surface area and to be higher in patients with MTHFR 677CC or 667CT genotype in the <i>MTHFR</i> gene. Point estimates for clearance (95% CI) were 145L/h (83-207) and 276L/h (250-302) in patients with the 667TT and the 677CT or 667CC, respectively. No relevant mutation in the <i>DPYD, TYMS, MTHFR </i>gene or pharmacokinetics was significantly associated with the occurrence of 5-FU adverse effect and with the changes in blood cell counts served as parameters for adverse event, respectively.<br /> In conclusion, the present study provides pharmacokinetic data on long-term 5-FU infusion and suggest a role of the MTHFR C677T polymorphism for 5-FU clearance, which however needs to be further investigated.