{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T13:24:54Z","timestamp":1783085094280,"version":"3.54.6"},"reference-count":19,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,9,19]],"date-time":"2020-09-19T00:00:00Z","timestamp":1600473600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Natalizumab is approved for multiple sclerosis treatment at a dose of 300 mg every 4 weeks. Extended\u2010interval dosing of natalizumab has been proposed as a strategy to mitigate the risk of progressive multifocal leukoencephalopathy, but the efficacy of extended\u2010interval dosing is not established. Previous models suggesting lower efficacy when initiating natalizumab treatment with extended\u2010interval dosing rather than every\u20104\u2010week dosing are inconsistent with reports from clinical observations and real\u2010world studies conducted in patient populations switching to extended\u2010interval dosing after a period of receiving natalizumab every 4\u00a0weeks. Here, the efficacy of natalizumab extended\u2010interval dosing was modeled specifically in patients switching from every\u20104\u2010week dosing to extended\u2010interval dosing. Published population pharmacokinetic\/pharmacodynamic models were used to simulate the distribution of alpha\u20104 integrin saturations for different body weight categories and dosing intervals (every 5, 6, 7, 8, 10, or 12 weeks). Generalized estimating equations relating alpha\u20104 integrin saturation to probability of multiple sclerosis lesion or relapse were derived from RESTORE trial data, which included patients (n = 175) who discontinued natalizumab after being treated every 4 weeks for \u22651 year and had no relapses in the year before discontinuation. The model\u2010based simulations described indicate that every\u20105\u2010week or every\u20106\u2010week dosing is likely to maintain the efficacy of natalizumab, particularly at body weights &lt;80 kg, in patients who switch after a period of stability on every\u20104\u2010week dosing. The efficacy of natalizumab decreases as dosing intervals and body weight increase. Partial model validation was achieved in that observed outcomes in an independent clinical study were similar to those predicted by the models.<\/jats:p>","DOI":"10.1002\/jcph.1737","type":"journal-article","created":{"date-parts":[[2020,9,19]],"date-time":"2020-09-19T18:29:41Z","timestamp":1600540181000},"page":"339-348","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Modeling the Efficacy of Natalizumab in Multiple Sclerosis Patients Who Switch From Every\u20104\u2010Week Dosing to Extended\u2010Interval Dosing"],"prefix":"10.1002","volume":"61","author":[{"given":"Ih","family":"Chang","sequence":"first","affiliation":[{"name":"Biogen Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kumar Kandadi","family":"Muralidharan","sequence":"additional","affiliation":[{"name":"Biogen Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nolan","family":"Campbell","sequence":"additional","affiliation":[{"name":"Biogen Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei\u2010Ran","family":"Ho","sequence":"additional","affiliation":[{"name":"Biogen Cambridge Massachusetts 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natalizumab\u2010associated PML in patients with MS is reduced with extended interval dosing","volume":"93","author":"Ryerson LZ","year":"2019","journal-title":"Neurology"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2015-312940"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.894"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000004485"},{"key":"e_1_2_10_14_1","volume-title":"Population pharmacokinetic modeling of natalizumab efficacy using body weight as a classification factor for extended interval dosing","author":"Muralidharan KK","year":"2016"},{"key":"e_1_2_10_15_1","volume-title":"No significant difference in relapse outcomes in patients switching to natalizumab extended interval dosing or remaining on standard interval dosing: propensity score comparative effectiveness analysis of patients in the Tysabri Observational Program","author":"Butzkueven 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