Farmacocinética poblacional de doxorubicina aplicada a la personalización de su dosificación en pacientes oncológicos

Abstract

ObjectiveTo develop and internally validate a population pharmacokinetic model for doxorubicin and to evaluate its predictive performance for dose individualization in cancer patients. MethodsDoxorubicin plasma concentrations were determined in thirty-three cancer patients treated with intravenous doxorubicin. A three-compartment pharmacokinetic model was implemented in the NONMEN VI programme to determine the doxorubicin pharmacokinetic parameters. The identifiability of the parameters was assessed by parametric bootstrap and model validation was performed using nonparametric bootstrap, visual predictive check, and numerical predictive check. The final model‘s predictive performance was evaluated in terms of accuracy and precision of plasma concentration predictions during the first and second cycles of chemotherapy. ResultsDoxorubicin clearance was 58.8L/h, with interpatient variability of 29.2% and intrapatient variability of 18.9%. The estimated volume of distribution at steady state was 2294L, with inter-and intrapatient variability of 7.3% and 26.1%, respectively. Internal validation confirmed that the population pharmacokinetic model is appropriate to describe the time course of the doxorubicin plasma concentrations and its variability in this population. The accuracy and precision of an a posteriori prediction of doxorubicin plasma concentrations improved by 63% and 41% compared to the a priori prediction. ConclusionThe Bayesian population pharmacokinetic model characterised the time course of doxorubicine plasma concentrations and can be accurately and precisely used to optimise doxorubicine dosing regimens in cancer patients.