Inter- and intra-patient variabilities of Michaelis-Menten parameters of 5-fluorouracil

C Terret, E Erdociain, R Guimbaud, T Lafont, R Bugat, P Canal, E Chatelut

Institut Claudius-Regaud, rue du Pont-St-Pierre, and Université Paul-Sabatier, F-31052 Toulouse, France

Introduction: Numerous studies described the non-linear pharmacokinetics of 5-FU. But, only few of them stated values for the in vivo pharmacokinetic parameters in human corresponding to the saturable metabolism of 5-FU : Vmax and Km for the maximal rate of elimination and the concentration at which the elimination rate was half of Vmax, respectively. Moreover, contradictory values have been proposed.

Objectives: The purpose of the study was to examine the inter- and intrapatient variability of Michaelis-Menten plasma parameters of 5-fluorouracil (5-FU) administered according to a schedule combining a bolus of 400 mg/m2 following by a 22-hour infusion of 600 mg/m2 for two consecutive days.

Patients and Methods: A pharmacokinetic population approach with the program system NONMEM was used in order to analyse the data from twenty one colorectal cancer patients.

Results: The 5-FU plasma concentrations versus time were best described by a two-compartment model with a non-linear elimination from the central compartment. The relationships between the pharmacokinetics parameters and patient characteristics were tested. On Day 1, the mean values (with inter-individual variability as expressed by the coefficient of variation) were 1390 mg.h-1 (20%), and 5.57 mg.L-1 (22%) for Vmax, and Km. Vmax was positively correlated to the body surface area and the percentage of liver involvement by metastatic disease. The mean plasma concentrations were higher during the second day of treatment although the administered 5-FU dosage was identical to that of Day 1. The analysis of this intra-patient variability showed that Km increased from Day 1 to Day 2, especially in the patients with low lymphocyte cell dihydropyrimidine dehydrogenase (DPD) activity, the enzyme that plays a major role in 5-FU liver catabolism.

Conclusion: The pharmacokinetic parameters obtained in this study would be useful to predict the 5-FU plasma concentrations following other schedules of administration of 5-FU, and also to analyse the pharmacokinetic data following administration of 5-FU prodrugs such as capecitabin when both unchanged drug and metabolites were quantified.

 

Reference: PAGE 9 (2000) Abstr 103 [www.page-meeting.org/?abstract=103]

Poster: poster