New model for gemcitabine and its metabolites
Sayar O.(1), Aldaz A. (1),Zufia L.(1), Viudez A.(2), Rifón J.(3), Nieto Y.(4)
(1) Pharmacy Department. University Clinic of Navarra, Pamplona, Spain. (2) Oncology Department, University Clinic of Navarra, Pamplona, Spain.(3) Hematology Department, University Clinic of Navarra, Pamplona, Spain. (4) Oncology Department, M.D. Anderson Cancer Center, University of Texas, USA.
Objectives: Gemcitabine is a prodrug with proved efficacy in different tumors as lung or pancreas cancer. It is intracellulary actived to bi- and triphosphate metabolites that inhibit processes required for DNA synthesis. Up to now there is not a proper model to fit simultaneously the parent drug and its metabolites. The optimization of this new model could improve clinic therapy with gemcitabine.
Methods: Analyses were performed with a mixed-effect pk model using NONMEM (Version V, level 1.1). Kinetics of Gemcitabine and its metabolites dFdU and dFdCTP was described using standard compartmental models.The model used to describe the plasma versus time profiles of dFdC, dFdU and intracellular dFdCTP includes a cell compartment. The plasma samples were obtained from 64 cancer patients in treatment with fixed-rate infusion of gemcitabine distributed in six cohorts with different times of infusion. Model discrimination was based on the minimum value of the objective function and visual inspection of the goodness of fit plots.
Results and conclusion: The monocompartimental model used by others authors to describe the kinetic of gemcitabine was appropiate to fit the plasma concentrations of parent drug. However this structural model described poorly plasma concentrations profiles of both active metabolites. The new model proposed contributes significantly to the optimization of the adjustment of the concentrations of three compounds relieving the limitations of the traditional model. Therefore its application could be a significant improvement in the clinical use of this drug because a limitant step gemcitabine efficacy is the saturation in the synthesis of the dFdCTP metabolite.