2003
   Verona, Italy

Comparison of the pharmacokinetics of S-1, an oral anticancer agent, in Western and Japanese patients

Emmanuelle Comets(1, 3), Kazumasa Ikeda(2), Yusuke Tanigawara(3)

(1) Inserm E0357, Hopital Bichat-Claude Bernard, Paris, France (2) Taiho Pharmaceutical Co, Ltd., Tokushima Research Center, Tokushima, Japan (3) Department of Pharmacy, Keio University Hospital, Tokyo, Japan

Objective: S-1 is an oral anticancer agent combining tegafur (FT), a prodrug of 5-fluorouracil (5-FU), with potassium oxonate (oteracil) and gimeracil (CDHP) respectively to mitigate gastrointestinal toxicity and increase the half-life of 5-FU. This article presents a population pharmacokinetic analysis of these four compounds in Western cancer patients. The second objective was to compare the pharmacokinetics of S-1 in Western patients to the pharmacokinetics in Japanese patients described in a previous analysis.

Methods: A single dose (25-45mg/m2) of S-1 was administered to 60 patients. In each patient, 6 concentrations of FT, 5-FU, oteracil and CDHP were measured over 24hr. Using NONMEM, oteracil and CDHP were analysed separately, and the individual estimates of CDHP parameters were included in the joint analysis of FT and 5-FU. We used validation techniques to assess differences between the two populations. Finally we compared the exposures in Western and Japanese patients using simulations, based on the results of the analyses performed in each population separately.

Results: A compartmental model describing the PK of the 4 compounds was developed. The influence of CDHP on the elimination of 5-FU was well described by an enzymatic inhibition model. The model provided a good fit for all compounds. The pharmacokinetics for oteracil were similar between Western and Japanese patients. Although the pharmacokinetics for FT were different between the two populations, apparent differences in exposure to its metabolite 5-FU resulted mostly from different total doses, due to different body sizes.