Population pharmacokinetics of gemcitabine and its metabolite in patients with cancer: effect of oxaliplatin and infusion rate

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Abstract

AIMS

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 (VC) 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 VC 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.

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