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

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. © 2007 The Authors.