A population pharmacokinetic model of methotrexate in paediatric patients with acute lymphoblastic leukaemia

• Autores: María José Moreno Fernández, Alejandro Pérez Pitarch, Rafael Ferriols Lisart, Manuel Alós Almiñana
• Localización: European journal of clinical pharmacy: atención farmacéutica, ISSN 2385-409X, Vol. 17, Nº. 3, 2015, pág. 3
• Idioma: inglés
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• Resumen

  • 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 2􀀙􀀏6,30 and 4􀀛8 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