Wakasugi Tetsuro
   Department   School of Medicine  Otorhinolaryngology-Head and Neck Surgery, Clinical Medical Sciences
Article types journal article
Language English
Peer review Peer reviewed
Title Pharmacokinetics of initial full and subsequent reduced doses of S-1 in patients with locally advanced head and neck cancer-effect of renal insufficiency.
Journal Formal name:Japanese journal of clinical oncology
Abbreviation:Jpn J Clin Oncol
ISSN code:14653621/03682811
Domestic / ForeginForegin
Volume, Issue, Page 47(5),407-412頁
Author and coauthor Yamazaki Tomoko, Tahara Makoto, Enokida Tomohiro, Wakasugi Tetsuro, Arahira Satoko, Zenda Sadamoto, Motegi Atsushi, Akimoto Tetsuo, Yoshisue Kunihiro
Publication date 2017/05
Summary Background:S-1 is a combination of tegafur [metabolized to 5-fluorouracil (5-FU)] with the modulators gimeracil (5-chloro-2,4-dihydroxypyridine) and oteracil potassium. 5-Chloro-2,4-dihydroxypyridine maintains plasma 5-FU concentrations by inhibiting dihydropyrimidine dehydrogenase, a pyrimidine catabolism enzyme that degrades 5-FU. As 50% of 5-chloro-2,4-dihydroxypyridine is excreted in urine, renal insufficiency may increase its blood level, increasing 5-FU concentrations. We investigated whether special dose modification is needed in the presence of renal insufficiency.Objective:We compared steady state pharmacokinetics of 5-FU for the initial S-1 dose and reduced doses in patients with head and neck cancer requiring dose reduction due to renal and non-renal toxicities.Methods:Chemoradiotherapy with S-1 and cisplatin was administered every 5 weeks for two courses with a radiation dose totaling 70 Gy over 33-35 fractions. Two additional courses of adjuvant chemotherapy were administered in the case of an objective response. The S-1 and/or cisplatin dose was reduced in response to renal, hematologic or other toxicities. The primary endpoint was the change in area under the plasma concentration-versus-time curve from time 0-10 hours (5-FU AUCss 0-10) between the initial and reduced S-1 doses.Results:Although the mean 5-FU levels in patients with non-renal toxicities significantly decreased between the full and reduced dose, the full-dose and reduced-dose mean maximum 5-FU plasma concentrations at steady state (Css max) and AUCss 0-10 in patients with renal insufficiency were similar.Conclusions:Standard S-1 dose reduction for renal toxicity did not result in a significant decrease in 5-FU levels at steady state. A greater reduction to lower plasma 5-chloro-2,4-dihydroxypyridine may be necessary in patients with renal insufficiency.
DOI 10.1093/jjco/hyx006
PMID 28159957