Population pharmacokinetics of methotrexate in Mexican pediatric patients with acute lymphoblastic leukemia

PurposeTo develop and validate a population pharmacokinetic model of Methotrexate (MTX) in Mexican children with acute lymphoblastic leukemia (ALL) for the design of personalized dosage regimens based on the anthropometric and physiological characteristics of each patient.MethodsA prospective study was developed in 50 children (1-15 years old) with ALL diagnosis attended at Pediatric Hemato-Oncology Service from Hospital Central "Dr. Ignacio Morones Prieto" and under treatment with high doses of MTX administered in 24-h continuous intravenous infusion. Plasma concentrations of MTX were determined in blood samples collected at 24, 36, 42 or 48 h post-infusion, by means of the CMIA immunoassay. The development of the population pharmacokinetic model was performed using the NONMEM (R) software evaluating the covariates that influence in clearance (CL), intercompartmental clearance (Q), central (V-c) and peripheral (V-p) volume of distribution of MTX.ResultsA two-compartment open model was selected to describe concentration-time data and body surface area (BSA) was the covariate that influences on MTX total CL. The population pharmacokinetic model obtained was: CL (L/h)=6.5xBSA(0.62), V-c (L)=0.36xWeight, Q (L/h)=0.41 and V-p (L)=3.2. Internal validation was performed by bootstrap and visual predictive check. Predictive performance of final model was evaluated by external validation in a different group of patients. Initial MTX dosing regimens were established by stochastic simulation with final population pharmacokinetic model.ConclusionsThe establishment of MTX dosing criteria in children with ALL should be adjusted based on the BSA of each patient to optimize oncological therapy and reduce the development of adverse effects. Therapeutic drug monitoring is an essential tool to individualize MTX doses to reduce toxicity and improve patients' outcomes.