{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T21:41:20Z","timestamp":1761514880253},"reference-count":14,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2022,4,4]],"date-time":"2022-04-04T00:00:00Z","timestamp":1649030400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Amyloid\u2010related imaging abnormalities with edema (ARIA\u2010E) have been reported in patients with early Alzheimer disease treated with aducanumab. ARIA\u2010E incidence has been observed to be dependent on both dose and apolipoprotein E4 carrier status. A time\u2010to\u2010event (TTE) approach applying data from 2 phase 3 studies (studies 301 and 302) was used to describe the effect of aducanumab serum exposure on the instantaneous risk of 2 end points: the first incidence of ARIA\u2010E and time to ARIA\u2010E resolution. A total of 3251 subjects with 826 events supported the TTE model to characterize the first ARIA\u2010E event. The TTE resolution model was supported by data from 768 of 826 subjects who had ARIA\u2010E resolved. Relationships between drug concentrations and ARIA\u2010E events were modeled with a hazard function dependent on time, aducanumab serum concentrations, attenuation of aducanumab exposure effects with time (ie, potential for tolerance to aducanumab exposure), study, and apolipoprotein E4 carrier status. The TTE model showed that ARIA\u2010E incidence rates were higher during the first 200 days, followed by a reduction in rates. The change in event rate reflects the attenuation of drug effect, thereby providing support for the current proposed titration regimen. Time to ARIA\u2010E resolution was characterized by a constant baseline hazard with a probability to resolution affected by baseline ARIA\u2010E severity and aducanumab concentration. ARIA\u2010E resolution was found to be driven primarily by baseline hazard and time and suggested that aducanumab concentration effect is a minor contributor to the time to resolution of ARIA\u2010E.<\/jats:p>","DOI":"10.1002\/jcph.2047","type":"journal-article","created":{"date-parts":[[2022,3,14]],"date-time":"2022-03-14T12:48:34Z","timestamp":1647262114000},"page":"1030-1046","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Time\u2010to\u2010Event Exposure\u2010Response Model for Amyloid\u2010Related Imaging Abnormalities Following Administration of Aducanumab to Subjects With Early Alzheimer Disease"],"prefix":"10.1002","volume":"62","author":[{"given":"Kumar Kandadi","family":"Muralidharan","sequence":"first","affiliation":[{"name":"Biogen  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sravan","family":"Karumanchi","sequence":"additional","affiliation":[{"name":"Ann Arbor Pharmacometrics Groups  Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth G.","family":"Kowalski","sequence":"additional","affiliation":[{"name":"Kowalski PMetrics Consulting LLC  Northville Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Burkett","sequence":"additional","affiliation":[{"name":"Biogen  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sunny","family":"Chapel","sequence":"additional","affiliation":[{"name":"Ann Arbor Pharmacometrics Groups  Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raj","family":"Rajagovindan","sequence":"additional","affiliation":[{"name":"Biogen  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan","family":"Nestorov","sequence":"additional","affiliation":[{"name":"Biogen  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,4,4]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072994"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(03)00294-0"},{"key":"e_1_2_13_4_1","unstructured":"US Food and Drug Administration.https:\/\/www.fda.gov\/news\u2010events\/press\u2010announcements\/fda\u2010grants\u2010accelerated\u2010approval\u2010alzheimers\u2010drug. 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