Prospective evaluation and refinement of an S-1 dosage formula based on renal function for clinical application

Masashi Takeuchi, Chiyo K. Imamura, Eisuke Booka, Hiroya Takeuchi, Takuro Mizukami, Takeshi Kawakami, Taro Funakoshi, Kazushige Wakuda, Yu Aoki, Yasuo Hamamoto, Minoru Kitago, Hirofumi Kawakubo, Narikazu Boku, Yusuke Tanigawara, Yuko Kitagawa

Research output: Contribution to journalArticlepeer-review

Abstract

In patients with impaired renal function, S-1–related toxicities increase due to higher exposure of 5-fluorouracil (5-FU). Our previous pharmacokinetic study in 16 cancer patients with various renal functions developed an S-1 dosage formula based on individual creatinine clearance (CLcr) and body surface area (BSA). To evaluate and refine the formula, this prospective study was conducted. Thirty-three patients with various renal functions received S-1 for 4 weeks at doses determined by the nomogram derived from the previously developed formula. A series of blood samples were collected after the first dose to calculate the area under the concentration-time curve (AUC) of 5-FU. Thirty patients with BSA of 1.14-1.84 m2 and CLcr of 23.8-96.4 mL/min were assessable for pharmacokinetics. The observed daily AUC ranged from 712.6 to 2868.7 ng·h/mL, and 18 patients achieved the target AUC (1447.8 ± 545.4 ng·h/mL). Three patients experienced S-1–related grade 3 adverse events during the first course. In the population pharmacokinetic analysis from the combined data of 46 patients in this study and the previous study, sex was identified as a statistically significant covariate for 5-FU clearance. Hence, the refined formula includes sex as an additional factor: Recommended daily dose = target AUC × (14.5 + 8.23 × SEX [0 for female and 1 for male] + 0.301 × CLcr) × BSA. Revised nomograms for recommended daily doses derived from the refined formula can be used in clinical practice to achieve the target AUC ensuring efficacy and safety of S-1.

Original languageEnglish
Pages (from-to)751-759
Number of pages9
JournalCancer science
Volume112
Issue number2
DOIs
Publication statusPublished - 2021 Feb

Keywords

  • S-1
  • dosage formula
  • nomogram
  • renal function
  • target AUC of 5-FU

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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