Population pharmacokinetics of methotrexate in Mexican pediatric patients with acute lymphoblastic leukemia
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To 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.
A 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® software evaluating the covariates that influence in clearance (CL), intercompartmental clearance (Q), central (Vc) and peripheral (Vp) volume of distribution of MTX.
A 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) = 6.5 × BSA0.62, Vc (L) = 0.36 × Weight, Q (L/h) = 0.41 and Vp (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.
The 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.
KeywordsMethotrexate Population pharmacokinetics Acute lymphoblastic leukemia Pediatric
The authors would like to thank for the assistance of Marlen Melendez, Mariana Morales and Malena Najera, as well as nurses, medical and technical staff from the Hemato-Oncology Pediatric Service at Hospital Central “Dr Ignacio Morones Prieto” and their contributions to the present study.
This work was supported by Joint Fund for the Promotion of Scientific and Technological Research (FOMIX) through National Council for Science and Technology and State Government from San Luis Potosí (Register FMSLP-2014-02-250277) and Sectorial Fund of Health Research and Social Security from National Council for Science and Technology (Register 272549).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
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