title: Development of an S-1 dosage formula based on renal function by a prospective pharmacokinetic study.
abstract: 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.
authors: Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors: Eisuke
authors: E
authors: Booka
authors: Department of Clinical Pharmacokinetics and Pharmacodynamics, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. imamurack@z3.keio.jp.
authors: Chiyo K
authors: CK
authors: Imamura
authors: Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors: Hiroya
authors: H
authors: Takeuchi
authors: Keio Cancer Center, Keio University Hospital, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors: Yasuo
authors: Y
authors: Hamamoto
authors: Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.
authors: Daisuke
authors: D
authors: Gomi
authors: Department of Clinical Oncology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan.
authors: Takuro
authors: T
authors: Mizukami
authors: First Department of Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.
authors: Takashi
authors: T
authors: Ichiyama
authors: First Department of Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.
authors: Kazunari
authors: K
authors: Tateishi
authors: Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.|Keio Cancer Center, Keio University Hospital, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors: Tsunehiro
authors: T
authors: Takahashi
authors: Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors: Hirofumi
authors: H
authors: Kawakubo
authors: Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors: Kenzo
authors: K
authors: Soejima
authors: Department of Clinical Oncology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan.
authors: Narikazu
authors: N
authors: Boku
authors: Department of Clinical Pharmacokinetics and Pharmacodynamics, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors: Yusuke
authors: Y
authors: Tanigawara
authors: Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.|Keio Cancer Center, Keio University Hospital, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors: Yuko
authors: Y
authors: Kitagawa
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004338:Drug Combinations; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics*; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010094:Oxonic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011379:Prognosis; D011446:Prospective Studies; D051437:Renal Insufficiency / Q000097:blood* / Q000139:chemically induced; D013274:Stomach Neoplasms / Q000097:blood / Q000188:drug therapy*; D005641:Tegafur / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D005472:Fluorouracil
keywords: Creatinine clearance; Dosage formula; Population pharmacokinetics; Renal function; S-1