{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T10:25:36Z","timestamp":1787221536605,"version":"build-2736575974"},"reference-count":53,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009399","name":"Peking University Third Hospital","doi-asserted-by":"publisher","award":["BYSYZD2021002"],"award-info":[{"award-number":["BYSYZD2021002"]}],"id":[{"id":"10.13039\/501100009399","id-type":"DOI","asserted-by":"publisher"}]},{"award":["BYSYZD2021002"],"award-info":[{"award-number":["BYSYZD2021002"]}],"id":[{"id":"https:\/\/ror.org\/04wwqze12","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009601","name":"Beijing Municipal Administration of Hospitals","doi-asserted-by":"publisher","award":["PX2024043"],"award-info":[{"award-number":["PX2024043"]}],"id":[{"id":"10.13039\/501100009601","id-type":"DOI","asserted-by":"publisher"}]},{"award":["PX2024043"],"award-info":[{"award-number":["PX2024043"]}],"id":[{"id":"https:\/\/ror.org\/04baakq55","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Prophylaxis in children with hemophilia B (HB) lacks quantitative approaches that integrate both plasma exposure and tissue distribution. This study aimed to develop and validate a physiologically based pharmacokinetic (PBPK) model of factor IX (FIX) for pediatric HB. The model incorporated the binding of FIX to type IV collagen (Col4) to characterize its distribution in both plasma and extravascular tissues. Methods: A total of 20 children with severe HB were included, contributing 219 plasma samples. The base PBPK model was first established and verified using adult and plasma-derived FIX (pdFIX) data. It was subsequently extrapolated to children by integrating FIX-CTBB parameters and pediatric observations for model calibration. The validated model was used to characterize plasma pharmacokinetics, predict tissue distribution and target attainment, and simulate alternative prophylactic dosing regimens. Results: The model adequately described the plasma pharmacokinetics of FIX in children and predicted substantial extravascular distribution. Total extravascular exposure was approximately sixfold higher than plasma exposure. Marked heterogeneity in target attainment was identified across tissues. Lower target attainment was observed in the colon, pancreas, and brain, whereas delayed attainment occurred in bone and muscle. Simulations of prophylactic dosing regimens suggested that 75 IU\/kg twice weekly may provide a favorable balance among sustained FIX exposure, tissue-level target attainment, and treatment burden. Conclusions: This PBPK model provides a mechanistic and quantitative framework for characterizing plasma and tissue exposure to FIX in children with HB and may support individualized optimization of FIX prophylactic dosing.<\/jats:p>","DOI":"10.3390\/pharmaceutics18081030","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:48:31Z","timestamp":1787219311000},"page":"1030","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Physiologically Based Pharmacokinetic (PBPK) Modeling of FIX in Pediatric Hemophilia B: Extravascular Distribution and Dosing Optimization"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9872-4212","authenticated-orcid":false,"given":"Mengmeng","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoqing","family":"Liu","sequence":"additional","affiliation":[{"name":"Hemophilia Comprehensive Care Center, Hematology Department, Beijing Children\u2019s Hospital, Capital Medical University, National Center for Children\u2019s Health, Beijing 100045, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qixian","family":"Ling","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongbo","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3275-261X","authenticated-orcid":false,"given":"Haojie","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runhui","family":"Wu","sequence":"additional","affiliation":[{"name":"Hemophilia Comprehensive Care Center, Hematology Department, Beijing Children\u2019s Hospital, Capital Medical University, National Center for Children\u2019s Health, Beijing 100045, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenping","family":"Chen","sequence":"additional","affiliation":[{"name":"Hemophilia Comprehensive Care Center, Hematology Department, Beijing Children\u2019s Hospital, Capital Medical University, National Center for Children\u2019s Health, Beijing 100045, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Libo","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1016\/S0140-6736(24)02139-1","article-title":"Haemophilia","volume":"405","author":"Chowdary","year":"2025","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e235","DOI":"10.1016\/S2352-3026(23)00067-4","article-title":"Haemophilia\u2014Unparalleled Progress but Inadequate Access","volume":"10","author":"Haematology","year":"2023","journal-title":"Lancet Haematol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1002\/cpt.83","article-title":"The Growing Number of Hemophilia Registries: Quantity vs. Quality","volume":"97","author":"Keipert","year":"2015","journal-title":"Clin. 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Pharmacol."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/8\/1030\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:53:10Z","timestamp":1787219590000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/8\/1030"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,20]]},"references-count":53,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["pharmaceutics18081030"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18081030","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,20]]}}}