Comparison of the Pharmacokinetics of S-1, an Oral Anticancer Agent, in Western and Japanese Patients

Emmanuelle Comets, Kazumasa Ikeda, Paulo Hoff, Pierre Fumoleau, Jantien Wanders, Yusuke Tanigawara

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

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 and Japanese patients. Methods: A single dose (25-45 mg/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 analyzed 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, and finally we compared the exposures in Western and Japanese patients using simulations. 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 5-FU and oteracil were similar between Western and Japanese patients, but apparent differences in exposure to 5-FU resulted from different total doses due to different body sizes.

Original languageEnglish
Pages (from-to)257-283
Number of pages27
JournalJournal of Pharmacokinetics and Pharmacodynamics
Volume30
Issue number4
DOIs
Publication statusPublished - 2003 Aug 1

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Keywords

  • 5-FU
  • Ethnic differences
  • Model validation
  • Oral anticancer drug
  • Population pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology

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