Does saturable formation of gemcitabine triphosphate occur in patients?
OBJECTIVE
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 microM) measured in this study.


CONCLUSIONS
The results showed that first-order and nonsaturable clearance described intracellular dFdCTP formation at clinically applied doses of gemcitabine.
Tham
Lai-San
LS
Department of Hematology-Oncology, National University Hospital, Singapore. tham_lai_san@lilly.com
Wang
Ling-Zhi
LZ
Soo
Ross A
RA
Lee
How-Sung
HS
Lee
Soo-Chin
SC
Goh
Boon-Cher
BC
Holford
Nicholas H G
NH
D000273:Adipose Tissue; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001711:Biotransformation; D001835:Body Weight; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism*; D017322:Clinical Trials, Phase II as Topic; D003404:Creatinine / Q000097:blood; D003570:Cytidine Triphosphate / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011355:Prodrugs / Q000493:pharmacokinetics*; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D003841:Deoxycytidine; D003570:Cytidine Triphosphate; C533693:gemcitabine triphosphate; D003404:Creatinine; D016190:Carboplatin; D000093542:Gemcitabine