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Understanding hemoglobin contribution to high-dose methotrexate disposition—population pharmacokinetics in pediatric patients with hematological malignancies

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Abstract

Purpose

The aim of the present study was to develop a population pharmacokinetic model for methotrexate (MTX) during high-dose treatment (HDMTX) in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin’s lymphoma (NHL) and to describe the influence of variability factors.

Methods

The study included 50 patients of both sexes (aged 1–18 years) who received 3 or 5 g/m2 of HDMTX. A nonlinear mixed effect modeling approach was applied for data analysis. Parameter estimation was performed by first-order conditional estimation method with interaction (FOCEI), whereas stepwise covariate modeling was used to assess variability factors.

Results

The final model is a two-compartment model that incorporates the effect of body surface area and the influence of hemoglobin and serum creatinine on MTX clearance (CL). Population pharmacokinetic values for a typical subject were estimated at 5.75 L/h/m2 for clearance (CL), 21.3 L/m2 for volume of the central compartment (V1), 8.2 L/m2 for volume of the peripheral compartment (V2), and 0.087 L/h/m2 for intercompartmental clearance (Q). According to the final model, MTX CL decreases with increasing serum creatinine, whereas a positive effect was captured for hemoglobin. A difference of almost 32% in MTX CL was observed among patients’ hemoglobin values reported in the study.

Conclusion

The developed population pharmacokinetic model can contribute to the therapy optimization during HDMTX in pediatric patients with ALL and NHL. In addition to renal function and body weight, it describes the influence of hemoglobin on CL, allowing better understanding of its contribution to the disposition of HDMTX.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This research was funded by the Ministry of Science, Technological Development and Innovation, Republic of Serbia, through Grant Agreement with the University of Belgrade-Faculty of Pharmacy (No: 451–03-47/2023–01/200161).

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Author notes

  1. Biljana Škorić and Marija Jovanović contributed equally to this paper and share first authorship.

Authors and Affiliations

  1. Department of Pharmacokinetics and Clinical Pharmacy, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221, Belgrade, Republic of Serbia

    Biljana Škorić, Marija Jovanović, Branislava Miljković & Katarina Vučićević

  2. University of Belgrade-School of Medicine, Belgrade, Republic of Serbia

    Miloš Kuzmanović

  3. Pediatric Clinic, Institute for Mother and Child Healthcare of Serbia “Dr Vukan Čupić”, Belgrade, Republic of Serbia

    Miloš Kuzmanović

Authors
  1. Biljana Škorić
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  4. Branislava Miljković
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  5. Katarina Vučićević
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Contributions

Conceptualization, research design, and project supervision: M.K. and K.V.; data curation: B.Š.; population analysis: M.J. and B.Š.; interpretation of the results: M.K., K.V., M.J., and B.Š.; writing—original draft preparation: M.J. and B.Š.; review and editing: M.K., B.M., and K.V. M.J. and B. Š. contributed equally to this paper and share first authorship. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Katarina Vučićević.

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The Ethics Committee of the Institute for Mother and Child Healthcare of Serbia “Dr Vukan Čupić” approved the study protocol and retrospective collection of data from medical records.

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Škorić, B., Jovanović, M., Kuzmanović, M. et al. Understanding hemoglobin contribution to high-dose methotrexate disposition—population pharmacokinetics in pediatric patients with hematological malignancies. Eur J Clin Pharmacol 80, 697–705 (2024). https://doi.org/10.1007/s00228-024-03642-4

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