{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T14:28:06Z","timestamp":1790605686522,"version":"4.1.0"},"reference-count":26,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2019,8,7]],"date-time":"2019-08-07T00:00:00Z","timestamp":1565136000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>To individualize treatment, phenytoin doses are adjusted based on free concentrations, either measured or calculated from total concentrations. As a mechanistic protein binding model may more accurately reflect the protein binding of phenytoin than the empirical Winter\u2013Tozer equation that is routinely used for calculation of free concentrations, we aimed to develop and validate a mechanistic phenytoin protein binding model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Data were extracted from routine clinical practice. A mechanistic drug protein binding model was developed using nonlinear mixed effects modelling in a development dataset. The predictive performance of the mechanistic model was then compared with the performance of the Winter\u2013Tozer equation in 5 external datasets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that in the clinically relevant concentration range, phenytoin protein binding is not only affected by serum albumin concentrations and presence of severe renal dysfunction, but is also concentration dependent. Furthermore, the developed mechanistic model outperformed the Winter\u2013Tozer equation in 4 out of 5 datasets in predicting free concentrations in various populations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Clinicians should be aware that the free fraction changes when phenytoin exposure changes. A mechanistic binding model may facilitate prediction of free phenytoin concentrations from total concentrations, for example for dose individualization in the clinic.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.14053","type":"journal-article","created":{"date-parts":[[2019,7,3]],"date-time":"2019-07-03T21:53:19Z","timestamp":1562190799000},"page":"2360-2368","source":"Crossref","is-referenced-by-count":17,"title":["Nonlinear protein binding of phenytoin in clinical practice: Development and validation of a mechanistic prediction model"],"prefix":"10.1111","volume":"85","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2185-8201","authenticated-orcid":false,"given":"Rob","family":"ter Heine","sequence":"first","affiliation":[{"name":"Radboud institute for Health Sciences &amp; Department of Pharmacy Radboudumc  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean P.","family":"Kane","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice Rosalind Franklin University of Medicine and Science  North Chicago IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alwin D.R.","family":"Huitema","sequence":"additional","affiliation":[{"name":"Department of Pharmacy &amp; Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands &amp; Department of Clinical Pharmacy, University Medical Center Utrecht Utrecht University  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew D.","family":"Krasowski","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Iowa Hospitals and Clinics  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik M.","family":"van Maarseveen","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Division of Laboratory Medicine and Pharmacy University Medical Center Utrecht, Utrecht University  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,8,7]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm00367a015"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2008.01561.x"},{"issue":"8","key":"e_1_2_9_4_1","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1093\/clinchem\/46.8.1132","article-title":"Evidence\u2010based implementation of free phenytoin therapeutic drug monitoring","volume":"46","author":"Burt M","year":"2000","journal-title":"Clin Chem"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01059685"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/00007691-200206000-00009"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1975.tb00475.x"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.34.3.395"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajcp\/98.1.19"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1177\/1060028016628166"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/00007691-198804000-00002"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0939-6411(99)00008-9"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2885.2002.00442.x"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.417"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arcmed.2004.11.006"},{"issue":"1","key":"e_1_2_9_16_1","first-page":"13","article-title":"Linking laboratory and medication data: new opportunities for pharmacoepidemiological research","volume":"45","author":"Berg MJ","year":"2007","journal-title":"Clin Chem Lab Med"},{"key":"e_1_2_9_17_1","unstructured":"The Nephron Information Center \u2010 Blood lab value comparison.http:\/\/nephron.org\/nephsites\/adp\/labvalues.html. 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