Development of a pharmacokinetic model to optimize the dosage regimen of TS-1, a combination preparation of tegafur, gimeracil and oteracil potassium.
BACKGROUND
TS-1 is a combination preparation of tegafur, a prodrug of 5-fluorouracil (5-FU), with gimeracil, a potent inhibitor of dihydropyrimidine dehydrogenase (DPD), which mediates the inactivation of 5-FU. UFT is a combination preparation of tegafur with uracil, which also inhibits DPD, though less potently; UFT has a higher content of tegafur than that in TS-1. We aimed to develop a pharmacokinetic model to describe the kinetics of tegafur and 5-FU after the administration of TS-1 and UFT.


METHODS
We developed a model incorporating the inhibition of DPD by gimeracil and uracil, and fitted the model to the observed kinetics of tegafur and 5-FU after the administration of TS-1 and UFT. Then, we simulated the plasma 5-FU profiles in patients with renal dysfunction and those after replacement of TS-1 with UFT and compared them with the observed profiles.


RESULTS
The developed model could appropriately describe the plasma concentration profiles of 5-FU and tegafur after the administration of TS-1 in patients with normal and impaired renal function.


CONCLUSIONS
The developed model may be useful to optimize the dosage regimen of TS-1 under various clinical conditions.
Inoue
Saori
S
Department of Medico-Pharmaceutical Sciences, Graduate School of Phamaceutical Sciences, Kyushu University, Fukuoka, Japan.
Ohtani
Hisakazu
H
Tsujimoto
Masayuki
M
Hori
Satoko
S
Sawada
Yasufumi
Y
D000284:Administration, Oral; D000465:Algorithms; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D003198:Computer Simulation; D004338:Drug Combinations; D005472:Fluorouracil / Q000097:blood; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008954:Models, Biological; D010094:Oxonic Acid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051437:Renal Insufficiency / Q000378:metabolism; D005641:Tegafur / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors; D014498:Uracil / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D011725:Pyridines; C079198:S 1 (combination); D005641:Tegafur; D014498:Uracil; D010094:Oxonic Acid; D005472:Fluorouracil; C104201:gimeracil