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Development of an S-1 dosage formula based on renal function by a prospective pharmacokinetic study
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 i...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Japan
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906077/ https://www.ncbi.nlm.nih.gov/pubmed/26304171 http://dx.doi.org/10.1007/s10120-015-0536-6 |
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author | Booka, Eisuke Imamura, Chiyo K. Takeuchi, Hiroya Hamamoto, Yasuo Gomi, Daisuke Mizukami, Takuro Ichiyama, Takashi Tateishi, Kazunari Takahashi, Tsunehiro Kawakubo, Hirofumi Soejima, Kenzo Boku, Narikazu Tanigawara, Yusuke Kitagawa, Yuko |
author_facet | Booka, Eisuke Imamura, Chiyo K. Takeuchi, Hiroya Hamamoto, Yasuo Gomi, Daisuke Mizukami, Takuro Ichiyama, Takashi Tateishi, Kazunari Takahashi, Tsunehiro Kawakubo, Hirofumi Soejima, Kenzo Boku, Narikazu Tanigawara, Yusuke Kitagawa, Yuko |
author_sort | Booka, Eisuke |
collection | PubMed |
description | 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10120-015-0536-6) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4906077 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Springer Japan |
record_format | MEDLINE/PubMed |
spelling | pubmed-49060772016-06-30 Development of an S-1 dosage formula based on renal function by a prospective pharmacokinetic study Booka, Eisuke Imamura, Chiyo K. Takeuchi, Hiroya Hamamoto, Yasuo Gomi, Daisuke Mizukami, Takuro Ichiyama, Takashi Tateishi, Kazunari Takahashi, Tsunehiro Kawakubo, Hirofumi Soejima, Kenzo Boku, Narikazu Tanigawara, Yusuke Kitagawa, Yuko Gastric Cancer Original Article 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10120-015-0536-6) contains supplementary material, which is available to authorized users. Springer Japan 2015-08-25 2016 /pmc/articles/PMC4906077/ /pubmed/26304171 http://dx.doi.org/10.1007/s10120-015-0536-6 Text en © The Author(s) 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Original Article Booka, Eisuke Imamura, Chiyo K. Takeuchi, Hiroya Hamamoto, Yasuo Gomi, Daisuke Mizukami, Takuro Ichiyama, Takashi Tateishi, Kazunari Takahashi, Tsunehiro Kawakubo, Hirofumi Soejima, Kenzo Boku, Narikazu Tanigawara, Yusuke Kitagawa, Yuko Development of an S-1 dosage formula based on renal function by a prospective pharmacokinetic study |
title | Development of an S-1 dosage formula based on renal function by a prospective pharmacokinetic study |
title_full | Development of an S-1 dosage formula based on renal function by a prospective pharmacokinetic study |
title_fullStr | Development of an S-1 dosage formula based on renal function by a prospective pharmacokinetic study |
title_full_unstemmed | Development of an S-1 dosage formula based on renal function by a prospective pharmacokinetic study |
title_short | Development of an S-1 dosage formula based on renal function by a prospective pharmacokinetic study |
title_sort | development of an s-1 dosage formula based on renal function by a prospective pharmacokinetic study |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906077/ https://www.ncbi.nlm.nih.gov/pubmed/26304171 http://dx.doi.org/10.1007/s10120-015-0536-6 |
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