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Population pharmacokinetic analyses of methotrexate in pediatric patients: a systematic review

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Abstract

Background and objectives

Methotrexate is widely utilized in the chemotherapy of malignant tumors and autoimmune diseases in the pediatric population, but dosing can be challenging. Several population pharmacokinetic models were developed to characterize factors influencing variability and improve individualization of dosing regimens. However, significant covariates included varied across studies. The primary objective of this review was to summarize and discuss population pharmacokinetic models of methotrexate and covariates that influence pharmacokinetic variability in pediatric patients.

Methods

Systematic searches were conducted in the PubMed and EMBASE databases from inception to 7 July 2023. Reporting Quality was evaluated based on a checklist with 31 items. The characteristics of studies and information for model construction and validation were extracted, summarized, and discussed.

Results

Eighteen studies (four prospective studies and fourteen retrospective studies with sample sizes of 14 to 772 patients and 2.7 to 93.1 samples per patient) were included in this study. Two-compartment models were the commonly used structural models for methotrexate, and the clearance range of methotrexate ranged from 2.32 to 19.03 L/h (median: 6.86 L/h). Body size and renal function were found to significantly affect the clearance of methotrexate for pediatric patients. There were limited reports on the role of other covariates, such as gene polymorphisms and co-medications, in the pharmacokinetic parameters of methotrexate pediatric patients. Internal and external evaluations were used to assess the performance of the population pharmacokinetic models.

Conclusion

A more rigorous external evaluation needs to be performed before routine clinical use to select the appropriate PopPK model. Further research is necessary to incorporate larger cohorts or pool analyses in specific susceptible pediatric populations to improve the understanding of predicted exposure profiles and covariate identification.

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Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

We thank all authors of the included studies for their hard work.

Funding

This work was supported by the National Natural Science Foundation of China (No. 81673510 and 82073936), Outstanding Scientific Fund of Shengjing Hospital (No. M0779), Natural Science Foundation of Fujian Province (No. 2021J01761), and Joint Funds for the Innovation of Science and Technology of Fujian Province (No. 2021Y9038).

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  1. Department of Pharmacy, Shengjing Hospital Affiliated to China Medical University, 36 Sanhao Street, Shenyang, 110004, Liaoning Province, China

    Yu Cheng, Yujia Zhang, Ying Zhang & Limei Zhao

  2. Department of Pharmacy, Fujian Medical University Union Hospital, 29 Xin Quan Rd, Gulou, Fuzhou, 350001, Fujian Province, People’s Republic of China

    Yu Cheng & Maobai Liu

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Contributions

Y.C. and LM.Z. designed the review and planned the work that led to the manuscript. Y.C., YJ.Z., and Y.Z.performed the literature search and data analysis. Y.C., MB.L., and LM.Z. drafted and revised the manuscript. All authors contributed to the work, approved of the submitted version, and voiced their support for the publishing of the manuscript.

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Correspondence to Maobai Liu or Limei Zhao.

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Cheng, Y., Zhang, Y., Zhang, Y. et al. Population pharmacokinetic analyses of methotrexate in pediatric patients: a systematic review. Eur J Clin Pharmacol (2024). https://doi.org/10.1007/s00228-024-03665-x

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