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

Abstract

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.

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 (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.

Figure 1

Diagnostic plot of population observed concentration vs. predicted concentration of gemcitabine (o, observed concentration; broken line, line of identity; solid line, regression line)

Figure 2

Diagnostic plot of population weighted residuals vs. predicted concentration of gemcitabine (o, observed concentration; broken line, zero line; solid line, regression line)

Figure 3

Diagnostic plot of population observed vs. predicted concentration of dFdU (o, observed concentration; broken line, line of identity; solid line, regression line)

Figure 4

Diagnostic plot of weighted residuals vs. predicted concentration of dFdU (o, observed concentration; broken line, zero line; solid line, line of identity)

Figure 5

Predictive check of gemcitabine concentration–time profile with 5th, 50th and 95th percentiles shown (o, observed concentrations). (Note: the first and second peaks derive from the 30-min and 100-min gemcitabine infusions, respectively.) These data were generated simultaneously. 5th percentile (), 50th percentile (), 95th percentile (), Observed (○)

Figure 6

Predictive check of dFdU concentration–time profile with 5th, 50th and 95th percentiles shown (o, observed concentrations). (Note: the first and second peaks derive from the 30-min and 100-min gemcitabine infusions, respectively.) These data were generated simultaneously. 5th percentile (), 50th percentile (), 95th percentile (), Observed (○)