{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T05:26:46Z","timestamp":1771046806130,"version":"3.50.1"},"reference-count":31,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2023,3,25]],"date-time":"2023-03-25T00:00:00Z","timestamp":1679702400000},"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":[[2023,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Publications on the exposure\u2010effect relationships of factor concentrates for hemophilia treatment are limited, whereas such analyses give insight on treatment efficacy. Our objective was to examine the relationship between the dose, factor VIII (FVIII) levels and bleeding for rFVIII\u2010SingleChain (lonoctocog alfa, Afstyla). Data from persons with severe hemophilia A on rFVIII\u2010SingleChain prophylaxis from three clinical trials were combined. The published rFVIII\u2010SingleChain population pharmacokinetic (PK) model was evaluated and expanded. The probability of bleeding was described with a parametric repeated time\u2010to\u2010event (RTTE) model. Data included 2080 bleeds, 2545 chromogenic stage assay, and 3052 one\u2010stage assay FVIII levels from 241 persons (median age 19\u2009years) followed for median 1090\u2009days. The majority of the bleeds occurred in joints (65%) and the main bleeding reason was trauma (44%). The probability of bleeding decreased during follow\u2010up and a FVIII level of 8.9\u00a0IU\/dL (95% confidence interval: 6.9\u201310.9) decreased the bleeding hazard by 50% compared to a situation without FVIII in plasma. Variability in bleeding hazard between persons with similar FVIII levels was large, and the pre\u2010study annual bleeding rate explained part of this variability. When a FVIII trough level of 1 or 3\u00a0IU\/dL is targeted during prophylaxis, simulations predicted two (90% prediction interval [PI]: 0\u201317) or one (90% PI: 0\u201311) bleeds per year, respectively. In conclusion, the developed PK\u2010RTTE model adequately described the relationship between dose, FVIII levels and bleeds for rFVIII\u2010SingleChain. The obtained estimates were in agreement with those published for the FVIII concentrates BAY 81\u20108973 (octocog alfa) and BAY 94\u20109027 (damoctocog alfa pegol), indicating similar efficacy to reduce bleeding.<\/jats:p>","DOI":"10.1002\/psp4.12938","type":"journal-article","created":{"date-parts":[[2023,3,25]],"date-time":"2023-03-25T20:02:09Z","timestamp":1679774529000},"page":"706-718","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Relationship between factor <scp>VIII<\/scp> levels and bleeding for <scp>rFVIII\u2010SingleChain<\/scp> in severe hemophilia A: A repeated time\u2010to\u2010event analysis"],"prefix":"10.1002","volume":"12","author":[{"given":"Laura H.","family":"Bukkems","sequence":"first","affiliation":[{"name":"Hospital Pharmacy\u2010Clinical Pharmacology Amsterdam University Medical Center  Amsterdam The\u00a0Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8240-0865","authenticated-orcid":false,"given":"Siv","family":"J\u00f6nsson","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Uppsala University  Uppsala Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marjon H.","family":"Cnossen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology Erasmus University Medical Center \u2010 Sophia Children's Hospital Rotterdam  Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1258-8297","authenticated-orcid":false,"given":"Mats O.","family":"Karlsson","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Uppsala University  Uppsala Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ron A. 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