{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T11:11:11Z","timestamp":1781608271389,"version":"3.54.5"},"reference-count":49,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T00:00:00Z","timestamp":1727913600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Type I interferons contribute to the pathogenesis of several autoimmune disorders, including systemic lupus erythematosus (SLE), systemic sclerosis, cutaneous lupus erythematosus, and myositis. Anifrolumab is a monoclonal antibody that binds to subunit 1 of the type I interferon receptor (IFNAR1). Results of phase IIb and phase III trials led to the approval of intravenous anifrolumab 300\u2009mg every 4\u2009weeks (Q4W) alongside standard therapy in patients with moderate\u2010to\u2010severe SLE. Here, we built a population physiology\u2010based pharmacokinetic (PBPK) model of anifrolumab by utilizing the physiochemical properties of anifrolumab, binding kinetics to the Fc gamma neonatal receptor, and target\u2010mediated drug disposition properties. A novel relative transcriptomics approach was employed to determine IFNAR1 expression in tissues (blood, skin, gastrointestinal tract, lungs, and muscle) using mRNA abundances from bioinformatic databases. The IFNAR1 expression and PBPK model were validated by testing their ability to predict clinical pharmacokinetics over a large dose range from different clinical scenarios after subcutaneous and intravenous anifrolumab dosing. The validated PBPK model predicted high unbound local concentrations of anifrolumab in blood, skin, gastrointestinal tract, lungs, and muscle, which exceeded its IFNAR1 dissociation equilibrium constant values. The model also predicted high IFNAR1 occupancy with subcutaneous and intravenous anifrolumab dosing. The model predicted more sustained IFNAR1 occupancy \u226590% with subcutaneous anifrolumab 120\u2009mg once\u2010weekly dosing vs. intravenous 300\u2009mg Q4W dosing. The results informed the dosing of phase III studies of anifrolumab in new indications and present a novel approach to PBPK modeling coupled with relative transcriptomics in simulating pharmacokinetics of therapeutic monoclonal antibodies.<\/jats:p>","DOI":"10.1002\/psp4.13245","type":"journal-article","created":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T10:30:00Z","timestamp":1727951400000},"page":"105-117","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Physiology\u2010based pharmacokinetic model with relative transcriptomics to evaluate tissue distribution and receptor occupancy of anifrolumab"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3415-8917","authenticated-orcid":false,"given":"Pradeep","family":"Sharma","sequence":"first","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences R&amp;D, AstraZeneca  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0668-7304","authenticated-orcid":false,"given":"David W.","family":"Boulton","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences 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 N.","family":"Bertagnolli","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences R&amp;D, AstraZeneca  Gaithersburg Maryland USA"}],"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 and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences R&amp;D, AstraZeneca  Gaithersburg Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,10,3]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27224"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/gene.2011.61"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0000000000000907"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000008128"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/lupus-2018-000261"},{"key":"e_1_2_11_7_1","unstructured":"Saphnelo Prescribing Information.https:\/\/den8dhaj6zs0e.cloudfront.net\/50fd68b9\u2010106b\u20104550\u2010b5d0\u201012b045f8b184\/44b6985c\u20108268\u201046b1\u2010ba3e\u20102bb43bfd4d4c\/44b6985c\u20108268\u201046b1\u2010ba3e\u20102bb43bfd4d4c_viewable_rendition__v.pdf. Accessed 15 Sep 2023."},{"key":"e_1_2_11_8_1","article-title":"EULAR recommendations for the management of systemic lupus erythematosus: 2023 update","author":"Fanouriakis A","year":"2023","journal-title":"Ann Rheum Dis"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-023-00909-5"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39962"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(19)30076-1"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1912196"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keab176"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.2055"},{"key":"e_1_2_11_15_1","unstructured":"ClinicalTrials.gov.Determine effectiveness of anifrolumab in systemic sclerosis (DAISY).https:\/\/clinicaltrials.gov\/study\/NCT05925803. Accessed 15 Sep 2023."},{"key":"e_1_2_11_16_1","unstructured":"ClinicalTrials.gov.A study to investigate the efficacy and safety of anifrolumab in adults with chronic and\/or subacute cutaneous lupus erythematosus (LAVENDER).https:\/\/classic.clinicaltrials.gov\/ct2\/show\/NCT06015737. Accessed 28 Nov 2023."},{"key":"e_1_2_11_17_1","unstructured":"AstraZeneca.A study to investigate the efficacy and safety of anifrolumab administered as subcutaneous injection and added to standard of care compared with placebo added to standard of care in adult participants with polymyositis (JASMINE).https:\/\/www.astrazenecaclinicaltrials.com\/study\/D3463C00003\/. Accessed 28 Nov 2023."},{"key":"e_1_2_11_18_1","unstructured":"ClinicalTrials.gov.Subcutaneous anifrolumab in adult patients with systemic lupus erythematosus (Tulip SC).https:\/\/clinicaltrials.gov\/study\/NCT04877691. Accessed 29 Nov 2023."},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1136\/lupus-2017-000252"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40271-017-0276-2"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1177\/2374373518770811"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2016.04.004"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0209587"},{"key":"e_1_2_11_24_1","unstructured":"ClinicalTrials.gov.Phase 3 Study of Anifrolumab in Adult Patients With Active Proliferative Lupus Nephritis (IRIS).https:\/\/www.clinicaltrials.gov\/study\/NCT05138133. Accessed 28 Nov 2023."},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar4492"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1080\/14397595.2019.1583833"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425250802691074"},{"key":"e_1_2_11_28_1","first-page":"670","article-title":"Prediction of the pharmacokinetics, pharmacodynamics, and efficacy of a monoclonal antibody, using a physiologically based pharmacokinetic FcRn model","volume":"5","author":"Chetty M","year":"2014","journal-title":"Front Immunol"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-014-9640-5"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-015-9819-4"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2017.03.038"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.111.043174"},{"key":"e_1_2_11_33_1","unstructured":"The Human Protein Atlas.https:\/\/www.proteinatlas.org\/ENSG00000142166\u2010IFNAR1\/tissue. 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