{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T22:26:33Z","timestamp":1757456793198,"version":"3.40.5"},"reference-count":50,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T00:00:00Z","timestamp":1713225600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["109\u20102813\u2010C\u2010002\u2010063\u2010B"],"award-info":[{"award-number":["109\u20102813\u2010C\u2010002\u2010063\u2010B"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000038","name":"U.S. Food and Drug Administration","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Pre\u2010emptive prediction to avoid myelosuppression and harmful sequelae is difficult given the complex interplay among patients, drugs and treatment protocols. This study aimed to model plasma and bone marrow concentrations and the likelihood of myelotoxicity following administration of 5\u2010fluorouracil (5\u2010FU) by diverse intravenous (IV) bolus or continuous infusion (cIF) regimens.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using physicochemical, in vitro and clinical data obtained from the literature consisting of various regimens and patient cohorts, a 5\u2010FU physiologically based pharmacokinetic (PBPK) model was developed. The predicted and observed PK values were compared to assess model performance prior to examining myelotoxicity potential of IV bolus <jats:italic>vs<\/jats:italic>. cIF and <jats:italic>DPYD<\/jats:italic> wild type <jats:italic>vs<\/jats:italic>. genetic variant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The established model was verified by utilizing 5\u2010FU concentration\u2013time profiles of adequate heterogeneity contributed by 36 regimens from 15 studies. The study provided corroborative evidence to explain why cIF (<jats:italic>vs<\/jats:italic>. IV bolus) had lower myelotoxicity risk despite much higher total doses. The PBPK model was used to estimate the optimal dosage in patients heterozygous for the <jats:italic>DPYD<\/jats:italic> c.1905\u2009+\u20091G\u2009&gt;\u2009A allele and suggested that a dose reduction of at least 25% was needed (compared to the dose in wild\u2010type subjects).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>A verified PBPK model was used to explain the lower myelotoxicity risk of cIF <jats:italic>vs<\/jats:italic>. IV bolus administration of 5\u2010FU and to estimate the dose reduction needed in carriers of a <jats:italic>DPYD<\/jats:italic> variant. With appropriate data, expertise and resources, PBPK models have many potential uses in precision medicine application of oncology drugs.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.16061","type":"journal-article","created":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T05:14:19Z","timestamp":1713330859000},"page":"1031-1040","source":"Crossref","is-referenced-by-count":4,"title":["Administration mode matters for 5\u2010fluorouracil therapy: Physiologically based pharmacokinetic evidence for avoidance of myelotoxicity by continuous infusion but not intravenous bolus"],"prefix":"10.1111","volume":"91","author":[{"given":"Chih\u2010Jia","family":"Chao","sequence":"first","affiliation":[{"name":"School of Pharmacy, College of Medicine National Taiwan University  Taipei Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iain","family":"Gardner","sequence":"additional","affiliation":[{"name":"Simcyp Division Certara UK Limited  Sheffield 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