Document Type
Article
Publication Date
3-2026
Identifier
DOI: 10.1007/s40262-026-01618-4; PMCID: PMC12960310
Abstract
BACKGROUND: High-dose methotrexate (HDMTX) is a key treatment for lymphoma with central nervous system involvement. Whether incorporating cystatin C into glomerular filtration rate estimation improves methotrexate (MTX) clearance prediction remains unclear.
OBJECTIVES: We aimed to evaluate whether cystatin C-inclusive glomerular filtration rate equations improve MTX clearance prediction and to explore the relationship between MTX exposure and acute kidney injury (AKI) in adult patients with lymphoma receiving HDMTX.
METHODS: This was a prospective single-center study performed on 80 adult patients with lymphoma receiving HDMTX (1.5-8 g/m2) over a 4-h infusion. A population pharmacokinetic model was constructed using data from 80 administrations of HDMTX and 427 serum MTX concentrations. The population pharmacokinetic model estimated MTX concentrations were included in a logistic regression to assess the relationship between MTX exposure and AKI.
RESULTS: A two-compartment model best described the pharmacokinetic data, with baseline albumin and CKD-EPI creatinine-cystatin C (eGFRCr-CysC) as significant covariates on clearance. Seventeen patients (21%) developed any-stage AKI. Among those receiving ≤ 3.5 g/m2, model-estimated 4-h MTX concentrations were associated with AKI (odds ratio: 1.02 per µmol/L; p = 0.0038), with an optimal threshold of 160 µmol/L (area under the concentration-time curve: 0.818). Patients above this threshold were 22 times more likely to experience AKI (p = 0.0005). This association was not observed in patients treated with 8 g/m2. Despite a lower dose and exposure, patients receiving ≤ 3.5 g/m2 demonstrated a stronger concentration-toxicity relationship.
CONCLUSIONS: Our results support the use of cystatin C-inclusive glomerular filtration rate estimates in MTX pharmacokinetic modeling and suggest early MTX concentration sampling may identify AKI risk, enabling proactive, AKI-mitigating clinical interventions during HDMTX therapy.
Journal Title
Clinical pharmacokinetics
Volume
65
Issue
3
First Page
465
Last Page
477
MeSH Keywords
Humans; Cystatin C; Methotrexate; Male; Female; Glomerular Filtration Rate; Middle Aged; Acute Kidney Injury; Prospective Studies; Models, Biological; Aged; Adult; Antimetabolites, Antineoplastic; Lymphoma; Metabolic Clearance Rate
PubMed ID
41606413
Keywords
Cystatin C; Methotrexate; Glomerular Filtration Rate; Acute Kidney Injury; Prospective Studies; Biological Models; Antimetabolites, Antineoplastic; Lymphoma; Metabolic Clearance Rate
Recommended Citation
Taylor ZL, Barreto EF, Cole KC, et al. Use of a Cystatin C-Based GFR Equation in a Population Pharmacokinetic Model of Methotrexate Clearance in Adult Patients with Lymphoma. Clin Pharmacokinet. 2026;65(3):465-477. doi:10.1007/s40262-026-01618-4
Comments
Grants and funding
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Publisher's Link: https://link.springer.com/article/10.1007/s40262-026-01618-4