Pharmacokinetics of initial full and subsequent reduced doses of S-1 in patients with locally advanced head and neck cancer-effect of renal insufficiency.
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.
Division of Head and Neck Medical Oncology, National Cancer Research Center Hospital East, Kashiwa, Chiba.
Tomoko
T
Yamazaki
Division of Head and Neck Medical Oncology, National Cancer Research Center Hospital East, Kashiwa, Chiba.
Makoto
M
Tahara
Division of Head and Neck Medical Oncology, National Cancer Research Center Hospital East, Kashiwa, Chiba.
Tomohiro
T
Enokida
Division of Head and Neck Medical Oncology, National Cancer Research Center Hospital East, Kashiwa, Chiba.
Tetsuro
T
Wakasugi
Department of Radiation Oncology, National Cancer Research Center Hospital East, Kashiwa, Chiba.
Satoko
S
Arahira
Department of Radiation Oncology, National Cancer Research Center Hospital East, Kashiwa, Chiba.
Sadamoto
S
Zenda
Department of Radiation Oncology, National Cancer Research Center Hospital East, Kashiwa, Chiba.
Atsushi
A
Motegi
Department of Radiation Oncology, National Cancer Research Center Hospital East, Kashiwa, Chiba.
Tetsuo
T
Akimoto
Pharmacokinetics Research Laboratories, Taiho Pharmaceutical Co., Ltd., Ibaraki, Taiho, Japan.
Kunihiro
K
Yoshisue
D000368:Aged; D019540:Area Under Curve; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D006258:Head and Neck Neoplasms / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010094:Oxonic Acid / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D051437:Renal Insufficiency / Q000150:complications*; D005641:Tegafur / Q000493:pharmacokinetics* / Q000627:therapeutic use*
D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D002945:Cisplatin
gimeracil; head and neck cancer; oxonic acid; pharmacokinetics; tegafur; toxicokinetics/area under curve