{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T03:31:33Z","timestamp":1790047893459,"version":"4.0.1"},"reference-count":33,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T00:00:00Z","timestamp":1726444800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Patients with severe and sometimes moderate hemophilia B are prophylactically treated with factor IX concentrates to prevent bleeding. For some time now, various extended terminal half\u2010life (EHL) recombinant factor IX concentrates are available allowing less frequent administration during prophylaxis in comparison to standard half\u2010life recombinant FIX (rFIX). Especially, recombinant FIX\u2010Fc fusion protein (rFIXFc; Alprolix\u00ae) exhibits a rapid distribution phase, potentially due to binding to type IV collagen (Col4) in the extravascular space. Studies suggest that the presence of extravascular rFIXFc is protective against bleeding as without measurable FIX activity in plasma, and no extra bleeding seems to occur. The physiologically based pharmacokinetic (PBPK) model for rFIXFc which we describe in this study, is able to accurately predict the observed concentration\u2010time profiles of rFIXFc in plasma and is able to quantify the binding of rFIXFc to Col4 in the extravascular space after an intravenous dose of 50\u2009IU\/kg rFIXFc in a male population. Our model predicts that the total AUC of rFIXFc bound to Col4 in the extravascular space is approximately 19 times higher compared to the AUC of rFIXFc in plasma. This suggests that rFIXFc present in the extravascular compartment may play an important role in achieving hemostasis after rFIXFc administration. Further studies on extravascular distribution of rFIXFc and the distribution profile of other EHL\u2010FIX concentrates are needed to evaluate the predictions of our PBPK model and to investigate its clinical relevance.<\/jats:p>","DOI":"10.1002\/psp4.13159","type":"journal-article","created":{"date-parts":[[2024,9,17]],"date-time":"2024-09-17T14:42:45Z","timestamp":1726584165000},"page":"1630-1640","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["<scp>PBPK<\/scp>\n                    modeling of recombinant factor\n                    <scp>IX<\/scp>\n                    Fc fusion protein (\n                    <scp>rFIXFc<\/scp>\n                    ) and\n                    <scp>rFIX<\/scp>\n                    to characterize the binding to type 4 collagen in the extravascular space"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2810-1570","authenticated-orcid":false,"given":"Michael E.","family":"Cloesmeijer","sequence":"first","affiliation":[{"name":"Department of Hospital Pharmacy\u2010Clinical Pharmacology Amsterdam UMC Location University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4318-6039","authenticated-orcid":false,"given":"Erik","family":"Sj\u00f6gren","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biosciences, Translational Drug Discovery and Development Uppsala University  Uppsala Sweden"},{"name":"Pharmetheus  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4536-2692","authenticated-orcid":false,"given":"Sjoerd F.","family":"Koopman","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy\u2010Clinical Pharmacology Amsterdam UMC Location University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7937-3429","authenticated-orcid":false,"given":"Peter. J.","family":"Lenting","sequence":"additional","affiliation":[{"name":"Laboratory for Hemostasis, Inflammation &amp; Thrombosis, Unit\u00e9 Mixed de Recherche (UMR)\u20101176, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (Inserm) Universit\u00e9 Paris\u2010Saclay  Le Kremlin\u2010Bic\u00eatre France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1557-2995","authenticated-orcid":false,"given":"Marjon H.","family":"Cnossen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology Erasmus MC \u2013 Sophia Children's Hospital, University Medical Center Rotterdam  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8401-0879","authenticated-orcid":false,"given":"Ron A. A.","family":"Math\u00f4t","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy\u2010Clinical Pharmacology Amsterdam UMC Location University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the OPTI\u2010CLOT study group and SYMPHONY consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,9,16]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1517\/14656566.2012.721780"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.14046"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-021-03111-2"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.mcb.2017.08.010"},{"key":"e_1_2_9_6_1","first-page":"1","article-title":"Type IV collagen drives alveolar epithelial\u2010endothelial association and the morphogenetic movements of septation","volume":"14","author":"Loscertales M","year":"2016","journal-title":"BMC Biol"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12959-016-0104-2"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.14300"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-017-9559-4"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12473"},{"key":"e_1_2_9_11_1","unstructured":"European Medicines Agency Alprolix product information.2021.https:\/\/www.ema.europa.eu\/en\/documents\/product\u2010information\/alprolix\u2010epar\u2010product\u2010information_en.pdf"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.32607\/20758251-2012-4-2-62-73"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12904"},{"key":"e_1_2_9_14_1","first-page":"751","article-title":"Modulation of extravascular binding of recombinant factor IX impacts the duration of efficacy in mouse models","volume":"123","author":"Machado SK","year":"2022","journal-title":"Thromb Haemost"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10930-014-9550-5"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.12969"},{"key":"e_1_2_9_17_1","unstructured":"European Medicines Agency.Benefix product information.2015."},{"key":"e_1_2_9_18_1","first-page":"1","article-title":"Evidence of clinically significant extravascular stores of factor IX","volume":"23","author":"Feng D","year":"2013","journal-title":"Bone"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2009.03545.x"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1097\/MBC.0000000000001230"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.15069"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2014.02.010"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-08-239665"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-013-0129-7"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/BCP.15881"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.12188"},{"key":"e_1_2_9_27_1","unstructured":"Simulations \u2013 Open Systems Pharmacology.https:\/\/docs.open\u2010systems\u2010pharmacology.org\/working\u2010with\u2010pk\u2010sim\/pk\u2010sim\u2010documentation\/pk\u2010sim\u2010simulations"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.2147\/JBM.S217539"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0040-1709522"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2022-168756"},{"key":"e_1_2_9_31_1","volume-title":"WHO characterization and application of physiologically based pharmacokinetic models","year":"2010"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtha.2023.11.023"},{"key":"e_1_2_9_33_1","article-title":"Extravascular distribution of conventional and Ehl FIX products using in\u00a0vivo SPECT imaging analysis in hemophilia B mice","volume":"130","author":"Salas J","year":"2017","journal-title":"Blood"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.15778"}],"container-title":["CPT: Pharmacometrics &amp; 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