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

Eisuke Booka, Chiyo Imamura, Hiroya Takeuchi, Yasuo Hamamoto, Daisuke Gomi, Takuro Mizukami, Takashi Ichiyama, Kazunari Tateishi, Tsunehiro Takahashi, Hirofumi Kawakubo, Kenzo Soejima, Narikazu Boku, Yusuke Tanigawara, Yuukou Kitagawa

Research output: Contribution to journalArticle

3 Citations (Scopus)

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<sup>2</sup>. 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 presented.)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.

Original languageEnglish
JournalGastric Cancer
DOIs
Publication statusAccepted/In press - 2015 Aug 25

Fingerprint

Fluorouracil
Pharmacokinetics
Prospective Studies
Kidney
Area Under Curve
Tegafur
Body Surface Area
Creatinine
Nomograms
Prodrugs
Theoretical Models
Incidence
Pharmaceutical Preparations
Population
Neoplasms
gimeracil

Keywords

  • Creatinine clearance
  • Dosage formula
  • Population pharmacokinetics
  • Renal function
  • S-1

ASJC Scopus subject areas

  • Oncology
  • Gastroenterology
  • Cancer Research

Cite this

Development of an S-1 dosage formula based on renal function by a prospective pharmacokinetic study. / Booka, Eisuke; Imamura, Chiyo; Takeuchi, Hiroya; Hamamoto, Yasuo; Gomi, Daisuke; Mizukami, Takuro; Ichiyama, Takashi; Tateishi, Kazunari; Takahashi, Tsunehiro; Kawakubo, Hirofumi; Soejima, Kenzo; Boku, Narikazu; Tanigawara, Yusuke; Kitagawa, Yuukou.

In: Gastric Cancer, 25.08.2015.

Research output: Contribution to journalArticle

Booka, Eisuke ; Imamura, Chiyo ; Takeuchi, Hiroya ; Hamamoto, Yasuo ; Gomi, Daisuke ; Mizukami, Takuro ; Ichiyama, Takashi ; Tateishi, Kazunari ; Takahashi, Tsunehiro ; Kawakubo, Hirofumi ; Soejima, Kenzo ; Boku, Narikazu ; Tanigawara, Yusuke ; Kitagawa, Yuukou. / Development of an S-1 dosage formula based on renal function by a prospective pharmacokinetic study. In: Gastric Cancer. 2015.
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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/m2. 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 presented.)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.",
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T1 - Development of an S-1 dosage formula based on renal function by a prospective pharmacokinetic study

AU - Booka, Eisuke

AU - Imamura, Chiyo

AU - Takeuchi, Hiroya

AU - Hamamoto, Yasuo

AU - Gomi, Daisuke

AU - Mizukami, Takuro

AU - Ichiyama, Takashi

AU - Tateishi, Kazunari

AU - Takahashi, Tsunehiro

AU - Kawakubo, Hirofumi

AU - Soejima, Kenzo

AU - Boku, Narikazu

AU - Tanigawara, Yusuke

AU - Kitagawa, Yuukou

PY - 2015/8/25

Y1 - 2015/8/25

N2 - 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/m2. 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 presented.)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.

AB - 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/m2. 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 presented.)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.

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KW - Dosage formula

KW - Population pharmacokinetics

KW - Renal function

KW - S-1

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