Population pharmacokinetics of methotrexate in paediatric patients with acute lymphoblastic leukaemia and malignant lymphoma

Abstract

1. This study aimed to identify physiological and pharmacogenomic covariates and develop a population pharmacokinetic model of high-dose methotrexate (HD-MTX) in Chinese paediatric patients with acute lymphoblastic leukaemia (ALL) and malignant lymphoma.

2. A total of 731 MTX courses and 1658 MTX plasm concentrations from 205 paediatric patients with ALL and malignant lymphoma were analysing using a non-linear mixed-effects model technique. 47 SNPs in 16 MTX-related genes were genotyped and screened as covariates. A PPK model was established to determine the influence of covariates, such as body surface area (BSA), age, laboratory test value, and SNPs on the pharmacokinetic process of HD-MTX.

3. Two-compartmental model with allometric scaling using BSA could nicely characterise the in vivo behaviour of HD-MTX. After accounting for body size, rs17004785 and rs4148416 were the covariates that influence MTX clearance (CL). The PPK model obtained was: CL = 9.33 * (BSA/1.73)^0.75 * e^{0.13*rs17004785} * e^{0.39*rs4148416} * e^ηCL, Vc = 24.98 * (BSA/1.73) * e^ηvc, Q = 0.18 * (BSA/1.73)^0.75 * e^ηQ and Vp = 4.70 * (BSA/1.73) * e^ηvp.

4. The established model combined with the Bayesian approach could estimate individual pharmacokinetic parameters and optimise personalised HD-MTX therapy for paediatric patients with ALL and malignant lymphoma.

Keywords:

• Methotrexate
• population pharmacokinetic model
• polymorphism
• paediatric
• acute lymphoblastic leukaemia
• lymphoma

Acknowledgements

The authors wish to sincerely thank the patients who participated in the research as well as their families; the medical team in charge of the patients.

Author contributions

MZ and XGL designed the study. XGL and YQS performed statistical and pharmacokinetic analysis. MZ and YQS wrote the manuscript. ZBC was in charge of the management of MTX concentrations measurements. FZ, HHW, and LZY contributed to the study design and revised the manuscript. All authors discussed and approved the final manuscript.

Disclosure statement

The authors report no declaration of interest.

Additional information

Funding

This study was funded by grant 7192060 from the Beijing Municipal Natural Science Foundation, Natural Science Foundation Youth Fund Project of Guangxi (2018JJB40051), and Liuzhou Science and Technology Plan Project (2019BJ10603).