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Tomoko Yamazaki, Makoto Tahara, Tomohiro Enokida, Tetsuro Wakasugi, Satoko Arahira, Sadamoto Zenda, Atsushi Motegi, Tetsuo Akimoto, Kunihiro Yoshisue, Pharmacokinetics of initial full and subsequent reduced doses of S-1 in patients with locally advanced head and neck cancer—effect of renal insufficiency, Japanese Journal of Clinical Oncology, Volume 47, Issue 5, May 2017, Pages 407–412, https://doi.org/10.1093/jjco/hyx006
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Abstract
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.
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.
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.
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.
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.
