Population pharmacokinetics of gemcitabine and its metabolite in patients with cancer: effect of oxaliplatin and infusion rate.
What is already known about this subject. Gemcitabine is an anticancer drug which is metabolized to a number of metabolites, administered using different dosing regimens and increasingly used in combination with oxaliplatin. the impact of dosing strategies and combination therapy on the pharmacokinetics of gemcitabine and its main metabolite is not clearly understood. what this study adds. this study has characterized the pharmacokinetics of gemcitabine and its main metabolite in people with cancer, including the variability between patients and on different occasions. gemcitabine metabolite (but not gemcitabine) pharmacokinetics were significantly affected by co-administration with oxaliplatin and were dependent on the order of administration. the clinical implications of this observation remain to be established.


OBJECTIVE
To characterize the population pharmacokinetics of gemcitabine and its metabolite (dfdu) in patients with cancer and identify factors that are influential in gemcitabine dose regimen design.


METHODS
Gemcitabine and dfdu plasma concentration-time and clinical data from 94 patients with cancer and nonlinear mixed effect modelling were used to characterize gemcitabine and metabolite pharmacokinetic variability and identify influential covariates.


RESULTS
Gemcitabine and dFdU pharmacokinetics were described by a two-compartment model with first-order elimination. The population mean (and between-subject variability, CV%) for clearance and volume of distribution of the central compartment (V(C)) for gemcitabine were 2.7 l min(-1) (31%) and 15 l (39%), respectively, and 0.04 l min(-1) (35%) and 46 l (15%), respectively, for dFdU. Oxaliplatin co-administration significantly decreased dFdU V(C) by 35% when gemcitabine was administered first and by 46% when oxaliplatin was administered first compared with patients who received gemcitabine alone.


CONCLUSIONS
Co-administration of gemcitabine with oxaliplatin significantly affected the pharmacokinetics of dFdU. The clinical significance of this observation in the context of gemcitabine safety and efficacy is worthy of further investigation.
Jiang
Xuemin
X
Faculty of Pharmacy, The University of Sydney, Sydney, NSW, Australia.
Galettis
Peter
P
Links
Matthew
M
Mitchell
Paul L
PL
McLachlan
Andrew J
AJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002986:Clinical Trials as Topic / Q000379:methods; D018592:Cross-Over Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000378:metabolism*; D000077150:Oxaliplatin; D000093542:Gemcitabine
D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000093542:Gemcitabine