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Pharmacokinetics and pharmacogenetics of high-dose methotrexate in Chinese adult patients with non-Hodgkin lymphoma: a population analysis

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Abstract

Purpose

High-dose methotrexate (HD-MTX) is widely used in the treatment of non-Hodgkin lymphoma (NHL), but the pharmacokinetic properties of HD-MTX in Chinese adult patients with NHL have not yet been established through an approach that integrates genetic covariates. The purposes of this study were to identify both physiological and pharmacogenomic covariates that can explain the inter- and intraindividual pharmacokinetic variability of MTX in Chinese adult patients with NHL and to explore a new sampling strategy for predicting delayed MTX elimination.

Methods

A total of 852 MTX concentrations from 91 adult patients with NHL were analyzed using the nonlinear mixed-effects modeling method. FPGS, GGH, SLCO1B1, ABCB1 and MTHFR were genotyped using the Sequenom MassARRAY technology platform and were screened as covariates. The ability of different sampling strategies to predict the MTX concentration at 72 h was assessed through maximum a posteriori Bayesian forecasting using a validation dataset (18 patients).

Results

A two-compartment model adequately described the data, and the estimated mean MTX clearance (CL) was 6.03 L/h (9%). Creatinine clearance (CrCL) was identified as a covariate for CL, whereas the intercompartmental clearance (Q) was significantly affected by the body surface area (BSA). However, none of the genotypes exerted a significant effect on the pharmacokinetic properties of MTX. The percentage of patients with concentrations below 0.2 µmol/L at 72 h decreased from 65.6 to 42.6% when the CrCL decreased from 90 to 60 ml/min/1.73 m2 with a scheduled dosing of 3 g/m2, and the same trend was observed with dose regimens of 1 g/m2 and 2 g/m2. Bayesian forecasting using the MTX concentrations at 24 and 42 h provided the best predictive performance for estimating the MTX concentration at 72 h after dosing.

Conclusions

The MTX population pharmacokinetic model developed in this study might provide useful information for establishing personalized therapy involving MTX for the treatment of adult patients with NHL.

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Funding

This study was supported by the Fujian Provincial Health Technology Project (No: 2018-ZQN-18), the Natural Science Foundation of Fujian Province (No: 2016J01509), and the Science and Technology Program of Fuiian Province, China (No: 2018Y2003).

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Authors and Affiliations

  1. Department of Pharmacy, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuma Road 420, Fuzhou, 350014, China

    Lin Yang, Juan Chen, Qiu-ling Zhao, Jing Huang & Rui-xiang Xie

  2. Department of Medical Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, China

    Hui Wu

  3. Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    Brenda C. M. de Winter

  4. Department of Pharmacy, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai, 200040, China

    Chang-cheng Sheng & Zheng Jiao

  5. Department of Pharmacy, Guizhou Provincial People’s Hospital, Guiyang, China

    Chang-cheng Sheng

  6. Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, China

    Hong-qiang Qiu & Yu Cheng

  7. Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University, No. 241 West Huaihai Road, Shanghai, 200030, China

    Zheng Jiao

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  1. Lin Yang
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  2. Hui Wu
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Correspondence to Zheng Jiao or Rui-xiang Xie.

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Yang, L., Wu, H., de Winter, B.C.M. et al. Pharmacokinetics and pharmacogenetics of high-dose methotrexate in Chinese adult patients with non-Hodgkin lymphoma: a population analysis. Cancer Chemother Pharmacol 85, 881–897 (2020). https://doi.org/10.1007/s00280-020-04058-4

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