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This prospective, observational, single\u2010center study evaluated adult patients with lymphoma treated with HDMTX. Samples were collected at predefined time points up to 96\u00a0h postinfusion. MTX and 7\u2010hydroxy\u2010MTX PKs were estimated by standard noncompartmental analysis. Linear regression determined which serum creatinine\u2010 or cystatin C\u2010based eGFR equation best predicted MTX clearance. The 80 included patients had a median (interquartile range [IQR]) age of 68.6\u00a0years (IQR 59.2\u201375.6), 54 (67.5%) were men, and 74 (92.5%) were White. The median (IQR) dose of MTX was 7.6 (IQR 4.8\u201311.3) grams. Median clearance was similar across three dosing levels at 4.5\u20135.6\u00a0L\/h and was consistent with linear PKs. Liver function, weight, age, sex, concomitant chemotherapy, and number of previous MTX doses did not impact clearance. MTX area under the curve (AUC) values varied over a fourfold range and appeared to increase in proportion to the dose. The eGFR<jats:sub>cys<\/jats:sub> (ml\/min) equation most closely correlated with MTX clearance in both the entire cohort and after excluding outlier MTX clearance values (<jats:italic>r<\/jats:italic> = 0.31 and 0.51, respectively). HDMTX as a 4\u2010h infusion displays high interpatient pharmacokinetic variability. Population PK modeling to optimize MTX AUC attainment requires further evaluation. The cystatin C\u2010based eGFR equation most closely estimated MTX clearance and should be investigated for dosing and monitoring in adults requiring MTX as part of lymphoma management.<\/jats:p>","DOI":"10.1111\/cts.13125","type":"journal-article","created":{"date-parts":[[2021,8,11]],"date-time":"2021-08-11T07:56:30Z","timestamp":1628668590000},"page":"105-117","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Prospective evaluation of high\u2010dose methotrexate pharmacokinetics in adult patients with lymphoma using\u00a0novel determinants of kidney function"],"prefix":"10.1111","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2146-5766","authenticated-orcid":false,"given":"Jason N.","family":"Barreto","sequence":"first","affiliation":[{"name":"Department of Pharmacy Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel M.","family":"Reid","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Oncology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4518-2309","authenticated-orcid":false,"given":"Carrie A.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Division of Hematology Department of Internal Medicine Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8783-0191","authenticated-orcid":false,"given":"Kristin C.","family":"Mara","sequence":"additional","affiliation":[{"name":"Division of Biomedical Statistics and Informatics Department of Health Sciences Research Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0338-7784","authenticated-orcid":false,"given":"Andrew D.","family":"Rule","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension Department of Internal Medicine Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2184-3683","authenticated-orcid":false,"given":"Kianoush B.","family":"Kashani","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension Department of Internal Medicine Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5651-1411","authenticated-orcid":false,"given":"Nelson","family":"Leung","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension Department of Internal Medicine Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas\u00a0R.","family":"Larson","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renee M.","family":"McGovern","sequence":"additional","affiliation":[{"name":"Department of Oncology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4215-6500","authenticated-orcid":false,"given":"Thomas E.","family":"Witzig","sequence":"additional","affiliation":[{"name":"Division of Hematology Department of Internal Medicine Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin F.","family":"Barreto","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Mayo Clinic  Rochester Minnesota USA"},{"name":"Robert D. and Patricia E. 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