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Association of genetic polymorphism in the folate metabolic pathway with methotrexate pharmacokinetics and toxicity in childhood acute lymphoblastic leukaemia and malignant lymphoma

  • Pharmacogenetics
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Abstract

Purpose

The objectives of this study were (1) to develop a population pharmacokinetic model of high-dose methotrexate (HD-MTX) in children with acute lymphoblastic leukaemia (ALL) and malignant lymphoma (ML) in order to investigate the influence of common polymorphisms in SLC19A1, MTHFR and ABCB1 on plasma levels of MTX and (2) to estimate MTX exposure in individual patients to study the association of genetic variability in the folate metabolic pathway with MTX toxicity.

Methods

The study population comprised 64 children with ALL/ML (age 1.6–16.8 years) who had received a total of 252 MTX courses (2–4 per patient). Common putative functional polymorphisms in the SLC19A1, MTHFR, MS, MTRR, TS and ABCB1 genes were analysed by PCR-based genotyping. Nonlinear mixed effects modelling was used for the pharmacokinetic analysis.

Results

The population typical value of clearance was 7.43 L/h (inter-individual variability 43.9%), central compartment volume was 16.7 L (46.6%), peripheral compartment volume was 2.6 L (63.3%) and distribution clearance was 0.0952 L/h (66.6%). MTX clearance decreased to 73.8% in patients with the MTHFR 677TT genotype. Patients homozygous for the variant MTHFR 1298A > C [odds ratio (OR) 0.14, 95% confidence interval (CI) 0.037–0.54] and SLC19A1 80A > G (OR 0.15, 95% CI 0.039-0.60) were at decreased risk for leucopenia. The TS 2R > 3R polymorphism was associated with a lower incidence of thrombocytopenia (OR 0.15, 95% CI 0.039–0.61) and mucositis (OR 0.016, 95% CI  0.0012-0.20). In contrast, the MTHFR 677TT polymorphism was associated with an increased incidence of mucositis (OR 23, 95% CI 2.1-240).

Conclusions

A population pharmacokinetic model developed in this study implies only a limited influence of genetic factors on the systemic disposition of MTX. Clearance is moderately reduced in patients with the MTHFR 677TT genotype. Genetic polymorphisms in the folate metabolic pathway and SLC19A1 were associated with HD-MTX toxicity.

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Acknowledgements

This work was financially supported by the Slovenian Research Agency (ARRS Grants P1-0189, P1-0170 and P3-0343).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Oncology and Haematology, University Children’s Hospital, University Medical Centre Ljubljana, Bohoričeva 20, Ljubljana, Slovenia

    Barbara Faganel Kotnik & Janez Jazbec

  2. Department of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, Ljubljana, Slovenia

    Iztok Grabnar

  3. Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, Ljubljana, Slovenia

    Petra Bohanec Grabar & Vita Dolžan

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  1. Barbara Faganel Kotnik
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  2. Iztok Grabnar
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  3. Petra Bohanec Grabar
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  4. Vita Dolžan
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  5. Janez Jazbec
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Corresponding author

Correspondence to Janez Jazbec.

Additional information

Barbara Faganel Kotnik and Iztok Grabnar contributed equally to the study

This study has been presented in part at the Population Approach Group Europe (PAGE) 2007 meeting in Copenhagen, Denmark (poster number: P3-11; available at: http://www.page-meeting.org/default.asp?abstract=1199).

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Faganel Kotnik, B., Grabnar, I., Bohanec Grabar, P. et al. Association of genetic polymorphism in the folate metabolic pathway with methotrexate pharmacokinetics and toxicity in childhood acute lymphoblastic leukaemia and malignant lymphoma. Eur J Clin Pharmacol 67, 993–1006 (2011). https://doi.org/10.1007/s00228-011-1046-z

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