J Clin Pharmacol. 2015 Aug;55(8):926-35. doi: 10.1002/jcph.499. Epub 2015 May 4.

Postgastrectomy pharmacokinetic changes of S-1 in patients with localized advanced gastric cancer.

Lim HS, Ryu KW, Lee JH, Kim YW, Ju Choi I, Kim MJ, Park YI, Hwang A, Park SR.

Abstract

S-1 is an oral 5-fluorouracil agent containing tegafur, 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate. This study explored the pharmacokinetics of S-1 and pharmacokinetic changes after gastric surgery in patients with resectable gastric cancer who received pre- and postoperative S-1 plus docetaxel. Serial blood was drawn before and after gastrectomy from 37 patients for pharmacokinetic analysis. The pharmacokinetics of tegafur, 5-fluorouracil, and CDHP were analyzed by noncompartmental analysis (NCA) methods and by modeling. In modeling analysis, CHDP concentrations were incorporated in the model as a time-varying covariate that inhibits the clearance of 5-fluorouracil following an inhibitory Emax model. In NCA, the pharmacokinetics of tegafur and 5-FU before and after gastric surgery were similar, although average maximum concentrations of 5-FU were decreased with statistical significance after gastrectomy. Median Tmax of tegafur was shorter after surgery without statistical significance. In modeling analysis, tegafur was best fitted by mixed zero and first-order absorption. The only difference in the final pharmacokinetic model around gastrectomy was the presence of an absorption lag of 0.23 hours before surgery. Incorporation of CDHP concentrations significantly improved the model. Although some pharmacokinetic results showed statistically significant changes after gastrectomy, these differences seem to be too small to have any clinical implication.

© 2015, The American College of Clinical Pharmacology.

KEYWORDS:

NONMEM; S-1; gastrectomy; modeling; pharmacokinetics

PMID:

25810324

DOI:

10.1002/jcph.499