{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:04:33Z","timestamp":1787317473728,"version":"build-2736575974"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T00:00:00Z","timestamp":1725408000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T00:00:00Z","timestamp":1725408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>An important aspect of improving care for people with hemophilia B (HB) is developing optimal treatment strategies. Here we aimed to provide in-silico evidence, comparing the estimated optimal posology of factor IX (FIX) products to support the patient-physician decision-making process. A population pharmacokinetic (popPK) model-based assessment comparing the performance of FIX products (rFIX, rIX-FP, rFIXFc, N9-GP) was developed. PopPK analyses were used to determine a product\u2019s optimal posology to target predefined steady-state FIX activity trough levels in a hypothetical population of 10,000 people with severe HB. Model-derived optimal posologies were compared across several parameters including trough levels, proportion of patients per regimen and consumption, considering 64 hypothetical patient scenarios of different FIX trough level targets and ages. Results indicated a marked difference between FIX products estimated to achieve target trough levels, consumption and dosing frequencies. rIX-FP was associated with higher trough levels than rFIX and rFIXFc, at a lower weekly dose and administration frequency, across all age groups. N9-GP use in adolescents and adults was associated with lower consumption compared with rIX-FP. Insights from this study may be utilized by clinicians to inform decision-making, by considering the model-generated estimated optimal posologies alongside multiple clinical factors and patient preferences.<\/jats:p>","DOI":"10.1038\/s41598-024-70784-x","type":"journal-article","created":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T23:35:17Z","timestamp":1725406517000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Pharmacokinetic model-based assessment of factor IX prophylaxis treatment regimens in severe hemophilia B"],"prefix":"10.1038","volume":"14","author":[{"given":"Bj\u00f6rn","family":"Vandewalle","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"Castaman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Teresa","family":"\u00c1lvarez-Rom\u00e1n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen Escuriola","family":"Ettingshausen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e1szl\u00f3","family":"Nemes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radovan","family":"Tomic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulo","family":"Martins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joana F.","family":"Rodrigues","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Pinachyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,9,4]]},"reference":[{"issue":"Suppl6","key":"70784_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/hae.14046","volume":"26","author":"A Srivastava","year":"2020","unstructured":"Srivastava, A. et al. WFH guidelines for the management of hemophilia. Haemophilia 26(Suppl6), 1\u2013158 (2020).","journal-title":"Haemophilia"},{"key":"70784_CR2","doi-asserted-by":"publisher","first-page":"2405","DOI":"10.1182\/blood-2012-05-429688","volume":"120","author":"E Santagostino","year":"2012","unstructured":"Santagostino, E. et al. Safety and pharmacokinetics of a novel recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in hemophilia B patients. Blood 120, 2405\u20132411 (2012).","journal-title":"Blood"},{"key":"70784_CR3","doi-asserted-by":"publisher","first-page":"2313","DOI":"10.1056\/NEJMoa1305074","volume":"369","author":"JS Powell","year":"2013","unstructured":"Powell, J. S. et al. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. N Engl. J. Med. 369, 2313\u20132323 (2013).","journal-title":"N Engl. J. Med."},{"key":"70784_CR4","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1182\/blood-2013-10-529974","volume":"123","author":"J Mahlangu","year":"2014","unstructured":"Mahlangu, J. et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood 123, 317\u2013325 (2014).","journal-title":"Blood"},{"key":"70784_CR5","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1111\/hae.12987","volume":"22","author":"KW Wyrwich","year":"2016","unstructured":"Wyrwich, K. W. et al. Changes in health-related quality of life with treatment of longer-acting clotting factors: Results in the A-LONG and B-LONG clinical studies. Haemophilia 22, 866\u2013872 (2016).","journal-title":"Haemophilia"},{"key":"70784_CR6","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1146\/annurev.me.36.020185.002225","volume":"36","author":"DJ Greenblatt","year":"1985","unstructured":"Greenblatt, D. J. Elimination half-life of drugs: Value and limitations. Annu. Rev. Med. 36, 421\u2013427 (1985).","journal-title":"Annu. Rev. Med."},{"key":"70784_CR7","unstructured":"FDA. Population pharmacokinetics guidance for industry https:\/\/www.fda.gov\/media\/128793\/download (2022)."},{"key":"70784_CR8","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1016\/j.jsps.2020.08.012","volume":"28","author":"A Alsultan","year":"2020","unstructured":"Alsultan, A. et al. Clinical pharmacology applications in clinical drug development and clinical care: A focus on Saudi Arabia. Saudi Pharm. J. 28, 1217\u20131227 (2020).","journal-title":"Saudi Pharm. J."},{"key":"70784_CR9","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1160\/TH15-08-0664","volume":"115","author":"R Ljung","year":"2016","unstructured":"Ljung, R. et al. Practical considerations in choosing a factor VIII prophylaxis regimen: Role of clinical phenotype and trough levels. Thromb. Haemost. 115, 913\u2013920 (2016).","journal-title":"Thromb. Haemost."},{"key":"70784_CR10","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1080\/17474086.2018.1489719","volume":"11","author":"G Castaman","year":"2018","unstructured":"Castaman, G. The benefits of prophylaxis in patients with hemophilia B. Expert Rev. Hematol. 11, 673\u2013683 (2018).","journal-title":"Expert Rev. Hematol."},{"key":"70784_CR11","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.blre.2018.01.001","volume":"32","author":"H Hazendonk","year":"2018","unstructured":"Hazendonk, H. et al. Setting the stage for individualized therapy in hemophilia: What role can pharmacokinetics play?. Blood Rev. 32, 265\u2013271 (2018).","journal-title":"Blood Rev."},{"key":"70784_CR12","doi-asserted-by":"publisher","first-page":"2305","DOI":"10.1111\/jth.12000","volume":"10","author":"PW Collins","year":"2012","unstructured":"Collins, P. W. et al. Population pharmacokinetic modeling for dose setting of nonacog beta pegol (N9-GP), a glycoPEGylated recombinant factor IX. J. Thromb. Haemost. 10, 2305\u20132312 (2012).","journal-title":"J. Thromb. Haemost."},{"key":"70784_CR13","doi-asserted-by":"publisher","first-page":"2132","DOI":"10.1111\/jth.13444","volume":"14","author":"Y Zhang","year":"2016","unstructured":"Zhang, Y. et al. Population pharmacokinetics of a new long-acting recombinant coagulation factor IX albumin fusion protein for patients with severe hemophilia B. J. Thromb. Haemost. 14, 2132\u20132140 (2016).","journal-title":"J. Thromb. Haemost."},{"key":"70784_CR14","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1007\/s00228-021-03111-2","volume":"77","author":"T Preijers","year":"2021","unstructured":"Preijers, T. et al. In silico comparison of pharmacokinetic properties of three extended half-life factor IX concentrates. Eur. J. Clin. Pharmacol. 77, 1193\u20131200 (2021).","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"70784_CR15","doi-asserted-by":"publisher","first-page":"204062072096688","DOI":"10.1177\/2040620720966888","volume":"11","author":"C Hermans","year":"2020","unstructured":"Hermans, C. & Dolan, G. Pharmacokinetics in routine haemophilia clinical practice: rationale and modalities-a practical review. Ther. Adv. Hematol. 11, 2040620720966888 (2020).","journal-title":"Ther. Adv. Hematol."},{"key":"70784_CR16","doi-asserted-by":"publisher","first-page":"e359","DOI":"10.1111\/hae.12969","volume":"22","author":"A Suzuki","year":"2016","unstructured":"Suzuki, A., Tomono, Y. & Korth-Bradley, J. M. Population pharmacokinetic modelling of factor IX activity after administration of recombinant factor IX in patients with haemophilia B. Haemophilia 22, e359-366 (2016).","journal-title":"Haemophilia"},{"key":"70784_CR17","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1007\/s40262-013-0129-7","volume":"53","author":"L Diao","year":"2014","unstructured":"Diao, L. et al. Population pharmacokinetic modelling of recombinant factor IX Fc fusion protein (rFIXFc) in patients with haemophilia B. Clin. Pharmacokinet. 53, 467\u2013477 (2014).","journal-title":"Clin. Pharmacokinet."},{"key":"70784_CR18","unstructured":"EMA. Refixia: EPAR - Assessment report https:\/\/www.ema.europa.eu\/en\/documents\/assessment-report\/refixia-epar-public-assessment-report_en.pdf (2016)."},{"key":"70784_CR19","unstructured":"EMC. Refixia 500 IU powder and solvent for solution for injection - Summary of Product Characteristics (SmPC) https:\/\/www.medicines.org.uk\/emc\/product\/9443\/smpc#gref (2017)."},{"key":"70784_CR20","doi-asserted-by":"publisher","DOI":"10.1002\/rth2.12661","volume":"6","author":"D Matino","year":"2022","unstructured":"Matino, D. et al. Switching to nonacog beta pegol in hemophilia B: Outcomes from a Canadian real-world, multicenter, retrospective study. Res. Pract. Thromb. Haemost. 6, e12661 (2022).","journal-title":"Res. Pract. Thromb. Haemost."},{"key":"70784_CR21","doi-asserted-by":"publisher","first-page":"900","DOI":"10.1016\/j.thromres.2014.02.010","volume":"133","author":"E Herzog","year":"2014","unstructured":"Herzog, E. et al. Biodistribution of the recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in rats. Thromb. Res. 133, 900\u2013907 (2014).","journal-title":"Thromb. Res."},{"key":"70784_CR22","unstructured":"EMA. Idelvion Summary of Product Characteristics (SmPC) https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/idelvion-epar-product-information_en.pdf (2022)."},{"key":"70784_CR23","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1111\/jth.14778","volume":"18","author":"ME Mancuso","year":"2020","unstructured":"Mancuso, M. E. et al. Long-term safety and efficacy of rIX-FP prophylaxis with extended dosing intervals up to 21 days in adults\/adolescents with hemophilia B. J. Thromb. Haemost. 18, 1065\u20131074 (2020).","journal-title":"J. Thromb. Haemost."},{"key":"70784_CR24","unstructured":"EMC. BeneFIX 250 IU powder and solvent for solution for injection - Summary of Product Characteristics (SmPC) https:\/\/www.medicines.org.uk\/emc\/product\/6157\/smpc#gref (2021)."},{"key":"70784_CR25","unstructured":"EMC. 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Blood 118, 2695\u20132701 (2011).","journal-title":"Blood"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-70784-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-70784-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-70784-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T23:37:08Z","timestamp":1725406628000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-70784-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,4]]},"references-count":27,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["70784"],"URL":"https:\/\/doi.org\/10.1038\/s41598-024-70784-x","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,4]]},"assertion":[{"value":"19 January 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 August 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 September 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"BV and PM are employed by Exigo Consultores, contracted by CSL Behring for the development of the research project.  GC has served on advisory committees\/speaker for Baxalta, Bayer, CSL Behring, Kedrion, Novo Nordisk, Pfizer, Roche, SOBI and UniQure and received research support from Pfizer, SOBI and CSL Behring.  MTAR has participated as speakers in advisory boards and sponsored symposia with Amgen, CSL Behring, Grifols, Novartis, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI and Takeda. CEE has acted as a consultant, and received speaker\u2019s fees and\/or research funding from Alnylam, Bayer, Biotest, CSL Behring, Grifols, Kedrion, Octapharma, Novo Nordisk, Roche, SOBI, Takeda,  LN has received speaker or consultancy fees from Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI and Takeda. RT, JR and KP are employees of CSL Behring.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"20534"}}