{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T10:36:22Z","timestamp":1787567782486,"version":"build-2736575974"},"reference-count":15,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T00:00:00Z","timestamp":1758931200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T00:00:00Z","timestamp":1758931200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100005614","name":"Biogen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005614","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>BIIB107 is a recombinant, humanized monoclonal antibody targeting \u03b14 integrin receptors, exhibiting a high binding affinity and strong receptor engagement potential in preclinical models, designed to prevent lymphocyte trafficking in multiple sclerosis (MS). This study aimed to characterize its pharmacokinetics (PK) and pharmacokinetic\u2013pharmacodynamic (PK\u2013PD) relationship using model\u2010based approaches to inform dose optimization. A Phase 1 study (NCT04593121) was conducted in 76 healthy volunteers who received single ascending doses intravenously or subcutaneously (SC), along with multiple ascending doses SC. Population PK and PK\u2013PD models were developed to quantify BIIB107 disposition and its effect on \u03b14 integrin receptor saturation. A sigmoidal Emax model was used to characterize the concentration\u2013effect relationship, and Monte Carlo simulations assessed dosing strategies for sustained \u03b14 integrin engagement. BIIB107 exhibited nonlinear, target\u2010mediated clearance, best described by a two\u2010compartment model with first\u2010order absorption and Michaelis\u2013Menten elimination. Body weight was included in the model using allometric scaling on clearance and volume of distribution\u2010related parameters. In a 70\u2010kg subject, key PK parameters included clearance, 7.28 mL\/h; central and peripheral compartment Vd, 3.01 and 1.18 L; terminal half\u2010life 19.3 days; and SC bioavailability 73.8%. PK\u2013PD analysis demonstrated dose\u2010dependent \u03b14 integrin saturation, with an EC50 of 0.376 \u00b5g\/mL. Simulations showed that 450 mg SC every 8 weeks maintained sustained \u03b14 integrin saturation \u226570%, the therapeutic threshold for efficacy, supporting this regimen for investigation in MS patients. These findings emphasize the value of model\u2010informed drug development in optimizing therapeutic monoclonal antibody doses and support BIIB107's further clinical advancement.<\/jats:p>","DOI":"10.1002\/jcph.70109","type":"journal-article","created":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T16:25:40Z","timestamp":1758990340000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dose Optimization of BIIB107, an Anti\u2010Alpha\u20104 Integrin Monoclonal Antibody, Through Population Pharmacokinetic and Pharmacodynamic Modeling"],"prefix":"10.1002","volume":"66","author":[{"given":"Marie","family":"Toukam","sequence":"first","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Biogen  Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Negin","family":"Karimian","sequence":"additional","affiliation":[{"name":"Clinical Development Biogen  Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eris","family":"Bame","sequence":"additional","affiliation":[{"name":"Biomarkers and Systems Biology Biogen  Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7131-6288","authenticated-orcid":false,"given":"Yan","family":"Xu","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Biogen  Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,27]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.38.10.1511"},{"issue":"6","key":"e_1_2_10_3_1","first-page":"S22","article-title":"Circulating adhesion molecules and inflammatory mediators in demyelination: a review","volume":"45","author":"Hartung HP","year":"1995","journal-title":"Neurology"},{"key":"e_1_2_10_4_1","unstructured":"Tysabri (Natalizumab) [prescribing information]. Biogen Inc. Accessed April 2025.https:\/\/www.tysabri.com\/content\/dam\/commercial\/tysabri\/pat\/en_us\/pdf\/tysabri_prescribing_information.pdf"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)99215-X"},{"key":"e_1_2_10_6_1","article-title":"Model\u2010informed reverse translational strategy to inform the clinical pharmacokinetics and first\u2010in\u2010human dose projection of HP1\/2: a humanized alpha\u20104\u2010integrin antibody","author":"Gaudreault F","year":"2019","journal-title":"ACOP Annual Meeting Abstracts"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/psp.2013.24"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1027382127079"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1011914508710"},{"key":"e_1_2_10_10_1","unstructured":"KarlssonMO HolfordN.A tutorial on visual predictive checks.Presented at: Population Approach Group in Europe (PAGE) Meeting;2008. 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Accessed April 3 2019.https:\/\/www.page\u2010meeting.org\/?abstract=1434."},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097\u20100258(19990315)18:5<581::AID\u2010SIM39>3.0.CO;2\u2010O"},{"key":"e_1_2_10_12_1","volume-title":"Pharmacokinetic and pharmacodynamic data analysis: concepts and applications","author":"Gabrielsson J","year":"2007"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa044397"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12224"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.2165\/11535960-000000000-00000"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.894"}],"container-title":["The Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.70109","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcph.70109","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.70109","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T09:43:31Z","timestamp":1787564611000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/jcph.70109"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,27]]},"references-count":15,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1002\/jcph.70109"],"URL":"https:\/\/doi.org\/10.1002\/jcph.70109","archive":["Portico"],"relation":{},"ISSN":["0091-2700","1552-4604"],"issn-type":[{"value":"0091-2700","type":"print"},{"value":"1552-4604","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,27]]},"assertion":[{"value":"2025-06-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70109"}}