TY - JOUR
T1 - Development of an S-1 dosage formula based on renal function by a prospective pharmacokinetic study
AU - Booka, Eisuke
AU - Imamura, Chiyo K.
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, Yuko
N1 - Funding Information:
Narikazu Boku has received honoraria and research funding from Taiho Pharmaceutical. Yusuke Tanigawara has served as a consultant for Taiho Pharmaceutical and Meiji Seika Pharma. Yuko Kitagawa has received grants from Otsuka Pharmaceutical, Taiho Pharmaceutical, Takeda Pharmaceutical, and Nippon Kayaku, and is a member of the speakers bureau for Taiho Pharmaceutical and Nippon Kayaku. The other authors declare that they have no conflict of interest.
Funding Information:
The study was performed as a project of the Promotion Plan for the Platform of Human Resource Development for Cancer by the Ministry of Education, Culture, Sports, Science and Technology in Japan. The study protocol was approved by each participating institution’s institutional review board and was registered in the University Hospital Medical Information Network Clinical Trials Registry under the number UMIN000011708. The study procedures were in accordance with the ethical standards of the Declaration of Helsinki. Written informed consent was obtained from all patients before their enrollment in the study.
Publisher Copyright:
© 2015, The Author(s).
PY - 2016/7/1
Y1 - 2016/7/1
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:${\text{dose}} = {\text{target AUC}} \times \left({21.9 + 0.375 \times {\text{CLcr}}} \right) \times {\text{BSA}},$dose=target AUC×(21.9+0.375×CLcr)×BSA,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:${\text{dose}} = {\text{target AUC}} \times \left({21.9 + 0.375 \times {\text{CLcr}}} \right) \times {\text{BSA}},$dose=target AUC×(21.9+0.375×CLcr)×BSA,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.
KW - Creatinine clearance
KW - Dosage formula
KW - Population pharmacokinetics
KW - Renal function
KW - S-1
UR - http://www.scopus.com/inward/record.url?scp=84939864027&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84939864027&partnerID=8YFLogxK
U2 - 10.1007/s10120-015-0536-6
DO - 10.1007/s10120-015-0536-6
M3 - Article
C2 - 26304171
AN - SCOPUS:84939864027
SN - 1436-3291
VL - 19
SP - 876
EP - 886
JO - Gastric Cancer
JF - Gastric Cancer
IS - 3
ER -
