High-dose methotrexate pharmacokinetics and its impact on prognosis of paediatric acute lymphoblastic leukaemia patients: A population pharmacokinetic study.
Xiaoxiao ChenJing LiLiting YuWenting HuJiaoyang CaiZhuo WangChangcheng ChenXin ZhangYangyang XieKefei WuYixiao MoJihui ChenShuhong ShenPublished in: British journal of haematology (2024)
This study delivers a comprehensive evaluation of the efficacy and pharmacokinetics of high-dose methotrexate (HDMTX) in a large cohort of Chinese paediatric acute lymphoblastic leukaemia patients. A total of 533 patients were included in the prognostic analysis. An association was observed between lower steady-state MTX concentrations (<56 μmol/L) and poorer outcomes in intermediate-/high-risk (IR/HR) patients. Subgroup analysis further revealed that this relationship between concentrations and prognosis was even more pronounced in patients with MLL rearrangements. In contrast, such an association did not emerge within the low-risk patient group. Additionally, utilizing population pharmacokinetic modelling (6051 concentrations from 815 patients), we identified the significant impact of physiological maturation, estimated glomerular filtration rate, sex and concurrent dasatinib administration on MTX pharmacokinetics. Simulation-based recommendations include a reduced dosage regimen for those with renal insufficiency and a specific 200 mg/kg dosage for infants under 1 year. The findings underscore the critical role of HDMTX in treating IR/HR populations and call for a reassessment of its application in lower-risk groups. An individualized pharmacokinetic dosage regimen could achieve the most optimal results, ensuring the largest proportion of steady-state concentrations within the optimal range.
Keyphrases
- end stage renal disease
- high dose
- ejection fraction
- chronic kidney disease
- newly diagnosed
- prognostic factors
- emergency department
- magnetic resonance imaging
- intensive care unit
- squamous cell carcinoma
- type diabetes
- computed tomography
- magnetic resonance
- adipose tissue
- liver failure
- radiation therapy
- patient reported outcomes
- case report
- small molecule
- single cell
- rectal cancer
- aortic dissection
- weight loss
- locally advanced