{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T18:39:59Z","timestamp":1791830399176,"version":"4.3.4"},"reference-count":28,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:p>In patients with systemic lupus erythematosus (SLE), increased type I interferon signaling is associated with increased disease activity across organs, including in the kidney, which can cause lupus nephritis (LN). Anifrolumab, which abrogates type I interferon signaling, is an approved treatment for moderate to severe SLE. In a phase 2 trial in patients with LN (TULIP\u2010LN; NCT02547922), promising clinical benefit was observed with an intensified regimen (IR) of intravenous anifrolumab (3\u00d7\u2009900\u2009mg Q4W, 300\u2009mg thereafter) compared with the approved SLE dose (basic regimen [BR], 300\u2009mg Q4W). Anifrolumab clearance was greater with higher levels of proteinuria; however, the quantitative relationship between proteinuria and anifrolumab exposure was not fully characterized. Here, we describe a mathematical model of time\u2010varying anifrolumab pharmacokinetics, 24\u2010hour urine protein\u2013creatinine ratio (UPCR24), and investigational product discontinuation in patients with LN. The model evaluated both TULIP\u2010LN anifrolumab dosing regimens (IR and BR) and revealed a temporal association between clearance and proteinuria in patients with LN, with each mg\/mg UPCR reduction resulting in a 21% decrease in linear anifrolumab clearance. Our model indicated that an intensified regimen including 6 initial anifrolumab 900\u2009mg doses provided adequate exposure and rapid UPCR24 reduction. Higher anifrolumab exposure and reduced UPCR24 were each associated with decreased risk of treatment discontinuation. These model results guided the selection of an optimized, longer intensified anifrolumab dosing regimen (6\u00d7\u2009900\u2009mg Q4W, 300\u2009mg thereafter) for the ongoing phase 3 IRIS trial (NCT05138133).<\/jats:p>","DOI":"10.1002\/cpt.70307","type":"journal-article","created":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T05:33:51Z","timestamp":1779514431000},"page":"429-439","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Anifrolumab Dose Regimen Selection for a Phase 3 Trial in Lupus Nephritis"],"prefix":"10.1002","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4745-9332","authenticated-orcid":false,"given":"Joachim","family":"Almquist","sequence":"first","affiliation":[{"name":"Clinical Pharmacology &amp; Quantitative Pharmacology Clinical Pharmacology &amp; Safety Sciences, BioPharmaceuticals R&amp;D  AstraZeneca Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0607-7247","authenticated-orcid":false,"given":"Yen Lin","family":"Chia","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology &amp; Quantitative Pharmacology Clinical Pharmacology &amp; Safety Sciences, BioPharmaceuticals R&amp;D  AstraZeneca, South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5506-4445","authenticated-orcid":false,"given":"Raj","family":"Tummala","sequence":"additional","affiliation":[{"name":"Late Respiratory and Immunology BioPharmaceuticals R&amp;D  AstraZeneca Gaithersburg Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3992-5620","authenticated-orcid":false,"given":"Lynn","family":"Bertagnolli","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology &amp; Quantitative Pharmacology Clinical Pharmacology &amp; Safety Sciences, BioPharmaceuticals R&amp;D  AstraZeneca Gaithersburg Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1712-0637","authenticated-orcid":false,"given":"David","family":"Jayne","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8261-8116","authenticated-orcid":false,"given":"Weifeng","family":"Tang","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology &amp; Quantitative Pharmacology Clinical Pharmacology &amp; Safety Sciences, BioPharmaceuticals R&amp;D  AstraZeneca Gaithersburg Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0533-7185","authenticated-orcid":false,"given":"Catharina","family":"Lindholm","sequence":"additional","affiliation":[{"name":"Late Respiratory and Immunology, BioPharmaceuticals R&amp;D  AstraZeneca Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39962"},{"key":"e_1_2_10_2_1","unstructured":"AstraZeneca: Saphnelo Prescribing Information(2021). <https:\/\/medicalinformation.astrazeneca\u2010us.com\/home\/prescribing\u2010information\/saphnelo.html>. Accessed April 4 2025."},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2022-002864"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(19)30076-1"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1912196"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kev311"},{"key":"e_1_2_10_7_1","article-title":"Increased risk of progression to lupus nephritis for lupus patients with elevated interferon signature","volume":"71","author":"Arriens C.R.Q.","year":"2019","journal-title":"Arthritis Rheumatol."},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241310636"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2015.159"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2021-221478"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2003.00840.x"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1177\/09612033221079771"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfz041"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-024-09907-w"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1177\/1060028018803587"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2024.116655"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.121"},{"key":"e_1_2_10_18_1","unstructured":"Food and Drug Administration: Saphnelo Prescribing Information(2021). <www.accessdata.fda.gov\/drugsatfda_docs\/label\/2021\/761123s000lbl.pdf>. 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