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A Systematic Review of Population Pharmacokinetic Models of Methotrexate

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objectives

Methotrexate (MTX) is widely used for the treatment of a variety of neoplastic and autoimmune diseases. However, its toxicity and efficacy varied greatly among individuals, and they could be predicted by its pharmacokinetics. Many population pharmacokinetic models have been published to describe MTX pharmacokinetics. The objective of this systematic review was to summarize and discuss covariates with significant influence on MTX pharmacokinetics.

Methods

We searched PubMed and EMBASE databases from their inception to April 2021 for population pharmacokinetic of MTX. The articles were screened by inclusion and exclusion criteria. The characteristics of studies and information for model construction and validation were extracted, summarized and discussed.

Results

Thirty-five articles were included. The two-compartment model well described the pharmacokinetic behavior of MTX. For inter-individual variability, an exponential distribution error model was usually used for high-dose MTX population pharmacokinetic models, while a proportional distribution error model was used for low-dose MTX population pharmacokinetic models. Proportional and combined proportional and additive error models were used to describe residual error. Renal function was an independent indicator of MTX clearance. Body weight, age, gene polymorphisms (SLCO1B1, ABCC2, ABCB1, ABCG2 and MTHFR) and co-medications (proton pump inhibitors, non-steroidal anti-inflammatory drug, dexamethasone, vancomycin, penicillin and salicylic acid) could influence MTX clearance. Body weight, body surface area, age and dosage regimen have significant influence on MTX central compartment volume. Internal bootstrap test, external validation and visual predictive check were used to evaluate model predictive ability.

Conclusions

Various covariates could affect MTX pharmacokinetics, and their relationships have been summarized and discussed. This review will be helpful for researchers to develop their own population pharmacokinetic models and select appropriate models for individualized therapy of MTX.

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Abbreviations

ALT :

Alanine transaminase

BSA :

Body surface area

BW :

Body weight

CLCR :

Creatinine clearance

CLMTX :

Methotrexate clearance

GFR:

Glomerular filtration rate

HD-MTX :

High-dose methotrexate

IIV:

Inter-individual variability

IOV:

Inter-occasion variability

LD-MTX:

Low-dose methotrexate

MTX:

Methotrexate

PopPK:

Population pharmacokinetics

QMTX :

Inter-compartmental clearance of methotrexate

SCR:

Serum creatinine

VcMTX :

Central compartment volume of methotrexate

VpMTX :

Peripheral compartment volume of methotrexate

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Acknowledgements

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

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Author notes

  1. Yiming Zhang and Liyu Sun contributed equally to this work and should be considered as co-first authors.

Authors and Affiliations

  1. Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, 119 Nansihuan West Road, Fengtai District, Beijing, 100070, People’s Republic of China

    Yiming Zhang, Liyu Sun, Zhigang Zhao & Shenghui Mei

  2. Department of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, People’s Republic of China

    Yiming Zhang, Liyu Sun, Xinwei Chen, Libo Zhao, Xiaoling Wang, Zhigang Zhao & Shenghui Mei

  3. Department of Pharmacy, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, 100045, People’s Republic of China

    Xinwei Chen, Libo Zhao & Xiaoling Wang

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  1. Yiming Zhang
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Correspondence to Zhigang Zhao or Shenghui Mei.

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Zhigang Zhao was supported by the Beijing Municipal Administration of Hospitals (ZYLX201827). Shenghui Mei was supported by the National Key R&D Program of China (2020YFC2008306) and Beijing Municipal Health Bureau (2018000021469G238).

Conflict of interest

Yiming Zhang, Liyu Sun, Libo Zhao, Xiaoling Wang, Zhigang Zhao and Shenghui Mei have no conflicts of interest.

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Author contributions

ZZ and MS designed the review and planned the work of the manuscript. YM and SL performed the literature search. MS and YM analyzed the extracted data. YM, SL, ZL, WY, ZZ and MS drafted and revised the manuscript. All authors approved the final version of this article.

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Zhang, Y., Sun, L., Chen, X. et al. A Systematic Review of Population Pharmacokinetic Models of Methotrexate. Eur J Drug Metab Pharmacokinet 47, 143–164 (2022). https://doi.org/10.1007/s13318-021-00737-6

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