Methotrexate-Induced Nephrotoxicity and Exposure Thresholds in Primary Central Nervous System Lymphoma: A Population...

High-dose methotrexate (HD-MTX)-induced nephrotoxicity remains a critical clinical challenge in primary central nervous system lymphoma (PCNSL) treatment, yet quantitative tools for individualized risk prediction are currently lacking. Here, a population pharmacokinetic/pharmacodynamic analysis was performed using 5,918 plasma concentration samples from 743 Chinese adult patients. Nonlinear mixed-effects modeling was employed to establish toxicodynamic structural models driven by MTX alone, 7-Hydroxy-MTX alone, or their combination. Although all models exhibited comparable predictive performance, the MTX linear model was selected as it offered the optimal balance between predictive performance and clinical feasibility. Covariate analysis identified hemoglobin as the most significant predictor, with higher levels correlating with reduced susceptibility to renal injury. To facilitate clinical translation, exposure-toxicity probability curves were constructed, enabling clinicians to identify dynamic concentration thresholds tailored to specific toxicity grades (Grade 1 vs. ≥2 nephrotoxicity) and individualized risk tolerance. Using a 10% risk probability for Grade ≥2 nephrotoxicity as the safety monitoring threshold, the corresponding MTX concentration thresholds at 24, 48, and 72 h were 9.71, 0.81, and 0.26 μmol/L, respectively. This quantitative framework serves as an exploratory tool to complement therapeutic drug monitoring, assisting in the early identification of MTX-induced renal injury among PCNSL patients with normal to mildly impaired renal function.