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

• Published in: Cancer chemotherapy and pharmacology 2020, Vol.85 (1), p.21-31
• Main Authors: Medellin-Garibay, Susanna E., Hernández-Villa, Nadia, Correa-González, Lourdes Cecilia, Morales-Barragán, Miriam Nayeli, Valero-Rivera, Karla Paulina, Reséndiz-Galván, Juan Eduardo, Ortiz-Zamudio, Juan José, Milán-Segovia, Rosa del Carmen, Romano-Moreno, Silvia
• Format: Article
• Language: English
• Subjects: Acute lymphoblastic leukemia; Anthropometry; Cancer Research; Children; Computer simulation; Dosage; Immunoassay; Intravenous administration; Intravenous infusion; Leukemia; Lymphatic leukemia; Medicine; Medicine & Public Health; Methotrexate; Oncology; Original Article; Patients; Pediatrics; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Population; Stochasticity; Therapeutic drug monitoring; Toxicity
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-019-03977-1

Purpose 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. Methods 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 ( V c ) and peripheral ( V p ) volume of distribution of MTX. Results 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 × BSA 0.62 , V c (L) = 0.36 × Weight, 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. Conclusions 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.