Resumen de A population pharmacokinetic model of methotrexate in paediatric patients with acute lymphoblastic leukaemia
María José Moreno Fernández, Alejandro Pérez Pitarch, Rafael Ferriols Lisart, Manuel Gerardo Alós Almiñana
Objective: To characterize the population pharmacokinetics of methotrexate (MTX) in paediatric patients with acute lymphoblastic leukaemia (ALL). The influence of biometric physiopathological and therapeutic variables upon residual and between-subject variability is also evaluated and an analysis is made of the capacity of the pharmacokinetic model to predict the experimental concentrations of the patients included in the study.
Method: A retrospective cohort study was made of paediatric patients receiving MTX in the form of a 24-hour intravenous perfusion as part of chemotherapy for ALL. The serum MTX concentrations were determined by fluorescence polarization immunoassay. Samples were collected 26,30 and 48 hours after the start of perfusion and then every 6-12 hours until reaching concentrations of under 0.09 mg/l. The population pharmacokinetic analysis was made using a non-linear mixed effects model with the NONMEM program. Internal validation of the model was made by bootstrapping and visual predictive check.
Results: Nine patients administered a total of 21 treatment cycles were included in the study. Monitoring of the serum MTX concentrations was performed in 82 samples. The selected pharmacokinetic model was a bicompartmental model.
The estimated pharmacokinetic parameters were: CL (clearance) = 6.7 l/h and Vc (central distribution volume) = 20.7 l. The between-subject variability of CL and Vc was 18.7 (%CV) and 28.2 (%CV) respectively. The residual variability was 22.2 (%CV). The final model included creatinine clearance and patient age as variables affecting MTX CL. The model presented adequate internal validity.
Conclusion: The pharmacokinetics of MTX in paediatric patients with ALL can be described by a bicompartmental model with first-order distribution and elimination. Creatinine clearance and patient age significantly influence the elimination of MTX. The selected pharmacostatistical model adequately predicts serum MTX concentration
