Development and Validation of a Population Pharmacokinetic Model of Methotrexate
Abstract Therapeutic drug monitoring is a strategy based on the determination of drugs’ plasma concentrations in biological fluids to individualize the dosage of drugs with a narrow therapeutic range. Methotrexate is a folic acid analogue used in at high-dose treatments of different types of leukemia, being a complex process due to the multitude of factors that affect its behavior. A population pharmacokinetic model of methotrexate in hematological patients developed in the Department of Pharmacy and Pharmaceutical Technology of the University of Salamanca has been evaluated. The model shows a high interindividual variability in the clearance and half-life of the patients evaluated, which justifies the need for methotrexate monitoring to establish their real dosage needs. On the other hand, it shows an intra-individual variability significantly lower than that corresponding to the inter-individual variability, which supports the use of the pharmacokinetic parameters estimated in previous cycles to estimate the doses in the following cycles with greater reliability.
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Puig L. Methotrexate: new therapeutic approaches. Actas Dermosifiliogr. 2014 jul.;105(6):583-89.
Rousseau A, Marquet P. Application of pharmacokinetic modelling to the routine therapeutic drug monitoring of anticancer drugs. Fundam Clin Pharmacol. 2002;16(4):253-62.
Zhang Y et al. A Systematic Review of Population Pharmacokinetic Models of Methotrexate. Eur J Drug Metab Pharmacokinet. 2022;47(2):143-64.
Aumente D et al. Population pharmacokinetics of high-dose methotrexate in children with acute lymphoblastic leukaemia. Clin Pharmacokinet. 2006;45(12):1227-38.
Igualada Quintanilla J, Romero Candel G, Tejada Cifuentes F. Metotrexato: toxicidad pulmonar, hepática y hematológica. Rev Clin Med Fam. 2016;9(3):159-66.
Lyashchenko AK, Cremers S. On precision dosing of oral small molecule drugs in oncology. Br J Clin Pharmacol. 2021;87(2):263-70.
Maksimovic, V. et al. Molecular mechanism of action and pharmacokinetic properties of methotrexate. Mol Biol Rep. 2020;47:4699-708.
Pitman SW, Frei E. Weekly methotrexate-calcium leucovorin rescue: effect of alkalinization on nephrotoxicity, pharmacokinetics in the CNS and use in CNS non-Hodgkin’s Lymphoma. Cancer Treat Rep. 1997;61(4):695-701.
Puig L. Methotrexate: new therapeutic approaches. Actas Dermosifiliogr. 2014 jul.;105(6):583-89.
Rousseau A, Marquet P. Application of pharmacokinetic modelling to the routine therapeutic drug monitoring of anticancer drugs. Fundam Clin Pharmacol. 2002;16(4):253-62.
Zhang Y et al. A Systematic Review of Population Pharmacokinetic Models of Methotrexate. Eur J Drug Metab Pharmacokinet. 2022;47(2):143-64.
Santiago, A., Pérez, S. J., & García, M. J. (2024). Development and Validation of a Population Pharmacokinetic Model of Methotrexate. FarmaJournal, 9(1), 63–71. https://doi.org/10.14201/fj2024916371
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