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Updated: Jul 27, 2025

Modeling Chemotherapy Resistant Leukemia In Vitro
Published on: February 9, 2016
Population Pharmacokinetic Model of Methotrexate in Brazilian Pediatric Patients with Acute Lymphoblastic Leukemia
Pricilla de Oliveira Henz1, Amanda Valle Pinhatti2,3, Lauro José Gregianin3
1Pharmacokinetics and PK/PD Modeling Laboratory, Pharmaceutical Sciences Graduate Program, Federal University of Rio Grande do Sul, 2752 Ipiranga Ave., Santana, RS, 90610-000, Porto Alegre, Brazil.
Objectives:
Methotrexate (MTX) is subject to therapeutic drug monitoring because of its high pharmacokinetic variability and safety risk outside the therapeutic window. This study aimed to develop a population pharmacokinetic model (popPK) of MTX for Brazilian pediatric acute lymphoblastic leukemia (ALL) patients who attended the Hospital de Clínicas de Porto Alegre, Brazil.
Methods:
The model was developed using NONMEM 7.4 (Icon®), ADVAN3 TRANS4, and FOCE-I. To explain inter-individual variability, we evaluated covariates from demographic, biochemical, and genetic data (single nucleotide polymorphisms [SNPs] related to the transport and metabolism of drugs).
Results:
A two-compartment model was built using 483 data points from 45 patients (0.33-17.83 years of age) treated with MTX (0.25-5 g/m2) in different cycles. Serum creatinine (SCR), height (HT), blood urea nitrogen (BUN) and a low BMI stratification (according to the z-score defined by the World Health Organization [LowBMI]) were added as clearance covariates. The final model described MTX clearance as [Formula: see text]. In the two-compartment structural model, the central and peripheral compartment volumes were 26.8 L and 8.47 L, respectively, and the inter-compartmental clearance was 0.218 L/h. External validation of the model was performed through a visual predictive test and metrics using data from 15 other pediatric ALL patients.
Conclusion:
The first popPK model of MTX was developed for Brazilian pediatric ALL patients, which showed that inter-individual variability was explained by renal function and factors related to body size.
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