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Here, a population pharmacokinetic\/pharmacodynamic analysis was performed using 5,918 plasma concentration samples from 743 Chinese adult patients. Nonlinear mixed\u2010effects modeling was employed to establish toxicodynamic structural models driven by MTX alone, 7\u2010Hydroxy\u2010MTX 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\u2013toxicity probability curves were constructed, enabling clinicians to identify dynamic concentration thresholds tailored to specific toxicity grades (Grade 1 vs. \u22652 nephrotoxicity) and individualized risk tolerance. Using a 10% risk probability for Grade \u22652 nephrotoxicity as the safety monitoring threshold, the corresponding MTX concentration thresholds at 24, 48, and 72\u2009h were 9.71, 0.81, and 0.26\u2009\u03bcmol\/L, respectively. This quantitative framework serves as an exploratory tool to complement therapeutic drug monitoring, assisting in the early identification of MTX\u2010induced renal injury among PCNSL patients with normal to mildly impaired renal function.<\/jats:p>","DOI":"10.1002\/cpt.70305","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T03:46:47Z","timestamp":1777952807000},"page":"245-256","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Methotrexate\u2010Induced Nephrotoxicity and Exposure Thresholds in Primary Central Nervous System Lymphoma: A Population\n                    <scp>PKPD<\/scp>\n                    Model"],"prefix":"10.1002","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9058-7895","authenticated-orcid":false,"given":"Ruoyun","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Pharmacy Beijing Tiantan Hospital, Capital Medical University  Beijing China"},{"name":"Department of Clinical Pharmacology, College of Pharmaceutical Sciences Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Beijing Tiantan Hospital, Capital Medical University  Beijing China"},{"name":"Department of Clinical Pharmacology, College of Pharmaceutical Sciences Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hematology Beijing Tiantan Hospital, Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Beijing Tiantan Hospital, Capital Medical University  Beijing China"},{"name":"Department of Clinical Pharmacology, College of Pharmaceutical Sciences Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiping","family":"Huo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Beijing Tiantan Hospital, Capital Medical University  Beijing China"},{"name":"Department of Clinical Pharmacology, College of Pharmaceutical Sciences Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongjie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Beijing Tiantan Hospital, Capital Medical University  Beijing China"},{"name":"Department of Clinical Pharmacology, College of Pharmaceutical Sciences Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefei","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Hematology Beijing Tiantan Hospital, Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhigang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Beijing Tiantan Hospital, Capital Medical University  Beijing China"},{"name":"Department of Clinical Pharmacology, College of Pharmaceutical Sciences Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Hematology Beijing Tiantan Hospital, Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenghui","family":"Mei","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Beijing Tiantan Hospital, Capital Medical University  Beijing China"},{"name":"Department of Clinical Pharmacology, College of Pharmaceutical Sciences Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"e_1_2_13_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-023-00439-0"},{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13600"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2015-0164"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1507547"},{"key":"e_1_2_13_5_1","article-title":"Risk factors associated with high\u2010dose methotrexate induced toxicities in primary central nervous system lymphoma","volume":"16","author":"Li W.","year":"2025","journal-title":"Front. 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