{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T15:40:37Z","timestamp":1784302837461,"version":"3.55.0"},"reference-count":31,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,7,9]],"date-time":"2023-07-09T00:00:00Z","timestamp":1688860800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:p>Methotrexate polyglutamates (MTX\u2010PG) concentrations in red blood cells (RBCs) have been suggested as a biomarker of response in patients with rheumatoid arthritis (RA) receiving low\u2010dose MTX therapy. We investigated the association and interpatient variability between RBC\u2010MTX\u2010PG<jats:sub>3\u20105<\/jats:sub>\u2010exposure and response in patients with RA starting MTX. Data of three prospective cohorts were available. The relationship between exposure and Disease Activity Score in 28 joints (DAS28) was analyzed using a population pharmacokinetic\u2010pharmacodynamic model. Relevant covariates were tested using full covariate modeling and backward elimination. From 395 patients, 3,401 MTX\u2010PG concentrations and 1,337 DAS28 measurements were available between 0 and 300\u2009days after MTX treatment onset. The developed model adequately described the time course of MTX\u2010PG<jats:sub>3\u20105<\/jats:sub> and DAS28. The median MTX\u2010PG<jats:sub>3\u20105<\/jats:sub> level at month 1 was 30.9\u2009nmol\/L (interquartile range (IQR): 23.6\u201343.7; <jats:italic>n<\/jats:italic>\u2009=\u200941) and at month 3: 69.3\u2009nmol\/L (IQR: 17.9\u201341.2; <jats:italic>n<\/jats:italic>\u2009=\u2009351). Clearance of MTX\u2010PG<jats:sub>3\u20105<\/jats:sub> from RBCs was 28% lower (95% confidence interval (CI): 23.6\u201332.8%) in a woman and 10% lower (95% CI: 7.7\u201312.4%) in a 65\u2010year\u2010old compared with a 35\u2010year\u2010old patient. MTX\u2010PG<jats:sub>3\u20105<\/jats:sub> concentrations associated with DAS28: half\u2010maximal effective concentration (EC<jats:sub>50<\/jats:sub>) was 9.14\u2009nmol\/L (95% CI: 4.2\u2009nmol\/L\u201014.1\u2009nmol\/L). EF at 80% (EC<jats:sub>80<\/jats:sub>) above 47\u2009nmol\/L was regarded as the optimal response. Independent of the MTX\u2010PG <jats:sub>3\u20135<\/jats:sub> \u2013 response association, co\u2010administration of disease\u2010modifying antirheumatic drugs and corticosteroids improved response (additive effect on maximum effect (<jats:italic>E<\/jats:italic><jats:sub>max<\/jats:sub>)), whereas smoking, high body mass index and low albumin decreased <jats:italic>E<\/jats:italic><jats:sub>max<\/jats:sub>. In patients with RA starting MTX, RBC\u2010MTX\u2010PG<jats:sub>3\u20105<\/jats:sub> was associated with clinical response. A dose increase is suggested when MTX\u2010PG<jats:sub>3\u20105<\/jats:sub> at month 1 is below 9.15\u2009nmol\/L, continued with the same dose when the concentration is above 47\u2009nmol\/L, and consider other treatment options above 78\u2009nmol\/L from 3\u00a0months onwards.<\/jats:p>","DOI":"10.1002\/cpt.2974","type":"journal-article","created":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T10:31:00Z","timestamp":1686738660000},"page":"893-903","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Methotrexate Polyglutamates Exposure \u2013 Response Modeling in a Large Cohort of Rheumatoid Arthritis Patients Starting Methotrexate"],"prefix":"10.1111","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6725-6719","authenticated-orcid":false,"given":"Renske C. F.","family":"Hebing","sequence":"first","affiliation":[{"name":"Amsterdam Rheumatology and Immunology Center Amsterdam UMC Location Reade  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9602-3407","authenticated-orcid":false,"given":"Imke H.","family":"Bartelink","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy and Clinical Pharmacology Amsterdam UMC  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9262-7411","authenticated-orcid":false,"given":"Helen R.","family":"Gosselt","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry Amsterdam University Medical Center \u2013 Location VUmc  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4737-5865","authenticated-orcid":false,"given":"Sandra G.","family":"Heil","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry Erasmus MC University Medical Center Rotterdam  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9213-107X","authenticated-orcid":false,"given":"Mauritis C. F. J.","family":"de Rotte","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry Amsterdam University Medical Center  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6628-6222","authenticated-orcid":false,"given":"Pascal H. P.","family":"de Jong","sequence":"additional","affiliation":[{"name":"Department of Rheumatology Erasmus Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6274-1934","authenticated-orcid":false,"given":"Mike T.","family":"Nurmohamed","sequence":"additional","affiliation":[{"name":"Amsterdam Rheumatology and Immunology Center Amsterdam UMC Location Reade  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3454-0094","authenticated-orcid":false,"given":"Robert","family":"de Jonge","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry Amsterdam University Medical Center \u2013 Location VUmc  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8401-0879","authenticated-orcid":false,"given":"Ron A. A.","family":"Math\u00f4t","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy and Clinical Pharmacology Amsterdam UMC  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,7,9]]},"reference":[{"key":"e_1_2_11_1_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-018-1645-5"},{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2008.092668"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-203725"},{"key":"e_1_2_11_4_1","first-page":"313","article-title":"Methotrexate polyglutamate levels in circulating erythrocytes and polymorphs correlate with clinical efficacy in rheumatoid arthritis","volume":"17","author":"Angelis\u2010Stoforidis P.","year":"1999","journal-title":"Clin. Exp. 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