Safety and efficacy of S-1, a novel oral fluorouracil antitumor drug, for a chronic renal failure patient maintained on hemodialysis.
OBJECTIVE
S-1 is a novel oral fluorouracil antitumor drug that combines three pharmacological agents: tegafur (FT), a prodrug of 5-fluorouracil (5-FU); 5-chloro-2,4-dihydroxypyridine (CDHP), an inhibitor of dihydropyrimidine dehydrogenase, and potassium oxonate (Oxo), a reducer of gastrointestinal toxicity. S-1 has safe and potent antitumor effects in patients with gastric cancer via these respective functions. However, the plasma 5-FU concentration is suspected to accumulate in patients with renal dysfunction, because 50% of the CDHP is excreted into the urine. There are no useful data on safety and efficacy of S-1 in chronic renal failure patients maintained on hemodialysis (HD). We examined the influence of HD on the pharmacokinetics (PK) of S-1 and its therapeutic efficacy in liver metastases from gastric cancer.


METHODS
For the HD patient, the dose of S-1 in a single-administration study was set at 50 mg/body/day (41.7% of the recommended dose of 80 mg/m2/day). S-1 was given to the patient 24 h after HD. Blood samples were obtained before administration and 2, 4, 6, 8, and 24 h thereafter and 1, 2, 4, and 72 h after the following HD session. The PK parameters (5-FU, CDHP, Oxo, and FT) were measured, and Cmax, Tmax, AUC0-24, and T1/2 were calculated. The dose of consecutive or maintained administrations was determined.


RESULTS
Both an increase in Cmax and an elongation of T1/2 for 5-FU, CDHP, and Oxo, but not for FT, occurred in this case as compared with controls. The AUC0-24 of 5-FU in this case was similar to that of controls at the standard dose. After HD, 87.8, 54.5, 77.4, and 66.2% of 5-FU, CDHP, Oxo, and FT, respectively, were eliminated. A slight accumulation of CDHP did not alter the 5-FU PK. Consecutive or maintained S-1 oral administration at the same dose showed similar effects on all PK parameters of a single-administration test. Liver metastases almost totally regressed with no adverse events 4 weeks after S-1 treatment (50 mg/body/day three times a week).


CONCLUSIONS
Adjusted doses of S-1 according to the results of PK studies may provide therapeutic safety and high efficacy in liver metastases from gastric cancer, even in chronic renal failure patients maintained on HD.
Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Kazunari
K
Tominaga
Kazuhide
K
Higuchi
Hirotoshi
H
Okazaki
Reiko
R
Suto
Masaki
M
Hamaguchi
Tetsuya
T
Tanigawa
Eiji
E
Sasaki
Masatsugu
M
Shiba
Toshio
T
Watanabe
Yasuhiro
Y
Fujiwara
Nobuhide
N
Oshitani
Takayuki
T
Matsumoto
Tetsuo
T
Arakawa
D000284:Administration, Oral; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005472:Fluorouracil / Q000008:administration & dosage* / Q000097:blood; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications* / Q000628:therapy*; D008113:Liver Neoplasms / Q000556:secondary; D008297:Male; D010094:Oxonic Acid / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006435:Renal Dialysis; D013274:Stomach Neoplasms / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D005641:Tegafur / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014057:Tomography, X-Ray Computed
D004338:Drug Combinations; D011725:Pyridines; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D005472:Fluorouracil