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The estimation of population PK\u2010PD parameters was performed using stochastic approximation expectation maximisation algorithm in Monolix 2021R2. The model was used to perform Monte Carlo simulations of a loading dose regimen (50mg subcutaneous methotrexate as loading doses, then 20mg weekly oral methotrexate) compared to a standard dosing regimen (10mg weekly oral methotrexate for 2\u2009weeks, then 20mg weekly oral methotrexate).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Every 40 nmol\/L increase in ery\u2010MTX\u2010PG<jats:sub>3\u20105<\/jats:sub> total concentration correlated with 1\u2010unit reduction in DAS\u201028\u20103. Significant covariate effects on the therapeutic response of methotrexate included the use of prednisolone in the first 4 weeks (positive use correlated with 25% reduction in DAS\u201028\u20103 when other variables were constant) and patient age (every 10\u2010year increase in age correlated with 3.4% increase in DAS\u201028\u20103 when other variables were constant). 4 methotrexate loading doses led to a higher percentage of patients achieving a good\/moderate response compared to the standard regimen (Week 4: 87.6% vs. 39.8%; Week 10: 64.7% vs. 57.0%).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>A loading dose regimen was more likely to achieve higher ery\u2010MTX\u2010PG concentration and better therapeutic response after 4 weeks of methotrexate treatment.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.16158","type":"journal-article","created":{"date-parts":[[2024,7,5]],"date-time":"2024-07-05T11:45:25Z","timestamp":1720179925000},"page":"2763-2780","source":"Crossref","is-referenced-by-count":8,"title":["Pharmacokinetic\u2010pharmacodynamic modelling and simulation of methotrexate dosing in patients with rheumatoid arthritis"],"prefix":"10.1111","volume":"90","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3660-6496","authenticated-orcid":false,"given":"Jiun Ming","family":"Tan","sequence":"first","affiliation":[{"name":"University of South Australia (UniSA: Clinical and Health Sciences, Centre for Pharmaceutical Innovation)  Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9996-4886","authenticated-orcid":false,"given":"Richard N.","family":"Upton","sequence":"additional","affiliation":[{"name":"Australian Centre for Pharmacometrics University of South Australia  Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7345-4084","authenticated-orcid":false,"given":"David J. 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