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Cancer Chemotherapy and Pharmacology

Published in:

01-12-2008 | Original Article

Does saturable formation of gemcitabine triphosphate occur in patients?

Authors: Lai-San Tham, Ling-Zhi Wang, Ross A. Soo, How-Sung Lee, Soo-Chin Lee, Boon-Cher Goh, Nicholas H. G. Holford

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2008

Abstract

Aim

This study aims to determine if intracellular formation of gemcitabine triphosphate (dFdCTP), an active metabolite of gemcitabine, is saturable at doses used for treatment of Asian patients with lung cancer.

Methods

From a phase II trial, plasma concentrations of gemcitabine, its inactive metabolite 2′-2′-difluorodeoxyuridine (dFdU), and mononuclear cell concentrations of gemcitabine-triphosphate were measured in 56 and 33 patients, respectively. The pharmacokinetics of gemcitabine and metabolites were modeled using nonlinear mixed effects modeling (NONMEM). A reduced dataset of ten randomly selected patients was employed to compare first-order and saturable formation of dFdCTP from gemcitabine.

Results

The median population clearance estimate for dFdCTP formation with the full dataset was 70.2 L/h/70 kg/1.7 m. Modeling Michaelis–Menten formation of dFdCTP on a reduced dataset estimated K _m to be 3.6 times higher than the maximum gemcitabine concentration (72.2 μM) measured in this study.

Conclusions

The results showed that first-order and nonsaturable clearance described intracellular dFdCTP formation at clinically applied doses of gemcitabine.

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Title: Does saturable formation of gemcitabine triphosphate occur in patients?
Authors: Lai-San Tham
Ling-Zhi Wang
Ross A. Soo
How-Sung Lee
Soo-Chin Lee
Boon-Cher Goh
Nicholas H. G. Holford
Publication date: 01-12-2008
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 1/2008
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-008-0707-9

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