Use of a Cystatin C-Based GFR Equation in a Population Pharmacokinetic Model of Methotrexate Clearance in Adult Patients with Lymphoma

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. 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. This was a prospective single-center study performed on 80 adult patients with lymphoma receiving HDMTX (1.5–8 g/m 2 ) 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. 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/m 2 , 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/m 2 . Despite a lower dose and exposure, patients receiving ≤ 3.5 g/m 2 demonstrated a stronger concentration–toxicity relationship. 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.