Development of an S-1 dosage formula based on renal function by a prospective pharmacokinetic study

Gastric Cancer. 2016 Jul;19(3):876-86. doi: 10.1007/s10120-015-0536-6. Epub 2015 Aug 25.


Background: S-1 is an oral anticancer drug, containing tegafur (a prodrug of 5-fluorouracil, 5-FU), 5-chloro-2,4-dihydroxypyridine, and potassium oxonate. As renal dysfunction is known to increase exposure of 5-FU following S-1 administration, the incidence of severe adverse reactions is increased in patients with impaired renal function. However, no reliable information on its dose modification for patients with renal dysfunction has been provided.

Methods: We conducted a prospective pharmacokinetic study to develop an S-1 dosage formula based on renal function. Sixteen cancer patients with various degrees of renal function received a single dose of S-1 at 40 mg/m(2). A series of blood samples were collected at predefined times within 24 h to assess the plasma concentration profiles of 5-FU, 5-chloro-2,4-dihydroxypyridine, and tegafur. A mathematical model for the relationship between renal function and exposure of 5-FU was constructed by a population pharmacokinetic analysis.

Results: The clearance of 5-FU following S-1 administration was related to body surface area and creatinine clearance in the range 15.9-108.8 mL/min as estimated by the Cockcroft-Gault equation. The S-1 dosage formula was derived as follows:[Formula: see text]where AUC is the area under the concentration-time curve, CLcr is creatinine clearance, and BSA is body surface area. The recommended daily doses of S-1 in Asia and Europe were also proposed as nomograms according to exposure matching to the previously reported area under the concentration-time curve of 5-FU, which confirmed the efficacy and toxicity in pivotal registration studies.

Conclusions: We have developed a novel formula for determining the S-1 dosage on the basis of renal function. Further validation is needed to confirm the formula for practical application.

Keywords: Creatinine clearance; Dosage formula; Population pharmacokinetics; Renal function; S-1.

MeSH terms

  • Aged
  • Antimetabolites, Antineoplastic / administration & dosage
  • Antimetabolites, Antineoplastic / adverse effects
  • Antimetabolites, Antineoplastic / pharmacokinetics*
  • Drug Combinations
  • Female
  • Fluorouracil / pharmacokinetics*
  • Follow-Up Studies
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Oxonic Acid / administration & dosage
  • Oxonic Acid / adverse effects
  • Oxonic Acid / pharmacokinetics*
  • Prognosis
  • Prospective Studies
  • Renal Insufficiency / blood*
  • Renal Insufficiency / chemically induced
  • Stomach Neoplasms / blood
  • Stomach Neoplasms / drug therapy*
  • Tegafur / administration & dosage
  • Tegafur / adverse effects
  • Tegafur / pharmacokinetics*
  • Tissue Distribution


  • Antimetabolites, Antineoplastic
  • Drug Combinations
  • S 1 (combination)
  • Tegafur
  • Oxonic Acid
  • Fluorouracil