{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T04:12:49Z","timestamp":1749010369256,"version":"3.41.0"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Model-informed personalized prophylaxis with factor VIII (FVIII) replacement therapy aimed at higher trough levels is becoming indispensable for patients with severe hemophilia A. This study aimed to identify the most suitable population pharmacokinetic (PK) models for personalized prophylaxis using various FVIII products and 2 clinical assays and to implement the most suitable one in open-access software.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Twelve published population PK models were systematically compared to predict the time above target (TaT) for a reference dosing occasion. External validation was performed using a 5-point PK data from 39 adult patients with hemophilia A with FVIII measured by chromogenic substrate (CSA) and 1-stage assays (OSAs) using NONMEM under 3 different conditions: a priori (with all FVIII samples blinded), a posteriori (with 1 trough sample), and general model fit (with all FVIII samples including the reference dosing occasion provided).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>On average, the baseline covariate models overpredicted TaT (a priori; bias \u22123.8 hours to 49.6 hours). When additionally including 1 previous trough FVIII sample before the reference dosing occasion (a posteriori), only 50% of the models improved in bias (\u22121.0 hours to 36.5 hours) and imprecision (22.4 hours and 60.7 hours). Using all the time points (general model fit), the models accurately predicted (individual TaT less than \u00b112 hours compared with the reference) 62%\u201390% and 33%\u201374% of the patients using CSA and OSA data, respectively. Across all scenarios, predictions using CSA data were more accurate than those using the OSA data.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>One model performed best across the population (bias: \u22123.8 hours a priori, \u22121.0 hours a posteriori<jats:italic toggle=\"yes\">,<\/jats:italic> and 0.6 hours <jats:italic toggle=\"yes\">general model fit<\/jats:italic>) and acceptably predicted 44% (a priori) to 90% (<jats:italic toggle=\"yes\">general model fit<\/jats:italic>) of the patients. To allow the community-based evaluation of patient\u2013individual FVIII dosing, this model was implemented in the open-access model-informed precision dosing software \u201cTDMx.\u201d<\/jats:p>\n          <\/jats:sec>","DOI":"10.1097\/ftd.0000000000000983","type":"journal-article","created":{"date-parts":[[2022,3,31]],"date-time":"2022-03-31T19:07:44Z","timestamp":1648753664000},"page":"665-673","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":2,"title":["Dosing for Personalized Prophylaxis in Hemophilia A Highly Varies on the Underlying Population Pharmacokinetic Models"],"prefix":"10.1097","volume":"44","author":[{"given":"David W.","family":"Uster","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Hamburg, Germany; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pratima","family":"Chowdary","sequence":"additional","affiliation":[{"name":"Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Riddell","sequence":"additional","affiliation":[{"name":"Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cecilia","family":"Garcia","sequence":"additional","affiliation":[{"name":"Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elsa","family":"Aradom","sequence":"additional","affiliation":[{"name":"Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Molly","family":"Musarara","sequence":"additional","affiliation":[{"name":"Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastian G.","family":"Wicha","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Hamburg, Germany; and"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"R1-20250603","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1056\/NEJM199401063300108","article-title":"Hemophilia A","volume":"330","author":"Hoyer","year":"1994","journal-title":"N Engl J Med."},{"key":"R2-20250603","first-page":"1","article-title":"An account of an hemorrhagic disposition existing in certain families","volume":"VI","author":"Otto","year":"1803","journal-title":"Med 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