{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T00:05:13Z","timestamp":1758931513112,"version":"3.44.0"},"reference-count":36,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T00:00:00Z","timestamp":1749427200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100008021","name":"Bristol-Myers Squibb Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008021","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br J Clin Pharmacol"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aims<\/jats:title><jats:p>Fedratinib is a potent, oral, Janus kinase inhibitor for the treatment of myelofibrosis (MF). This report describes exposure\u2013response (E\u2013R) analyses of fedratinib based on pooled data from phase 2\/3 studies in patients with intermediate\u20102 or high\u2010risk MF, with or without prior ruxolitinib exposure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Pharmacokinetic (PK) exposures were derived from the population PK analysis. Efficacy endpoints included spleen volume reduction \u226535% (SVR35) and total symptom score reduction \u226550% (TSS response). Safety endpoints included grade \u22653 anaemia or thrombocytopenia, any\u2010grade nausea\/vomiting and diarrhoea. The E\u2013R models were developed using logistic regression analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Fedratinib exposure was positively associated with SVR35 (odds ratio [OR], 38.2; 95% confidence interval [CI], 12.4\u2013118; <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001) and TSS response (OR, 20.8; 95% CI, 6.27\u201369.2; <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001), after adjusting for covariates. Baseline spleen volume was inversely associated with SVR35 (<jats:italic>P<\/jats:italic>\u2009=\u20090.029). Prior ruxolitinib exposure was not associated with SVR35 (<jats:italic>P<\/jats:italic>\u2009=\u20090.090) or TSS response (<jats:italic>P<\/jats:italic>\u2009=\u20090.326). Although numerically higher incidence of adverse events was observed in patients with higher fedratinib exposure, there was no statistically significant association between fedratinib exposure and any safety related endpoints. Prior ruxolitinib exposure was associated with experiencing grade \u22653 thrombocytopenia (<jats:italic>P<\/jats:italic>\u2009=\u20090.004). Lower baseline haemoglobin level (&lt;10\u00a0g\/dL) and platelet count (&lt;100\u2009\u00d7\u200910<jats:sup>9<\/jats:sup>\/L) were associated with experiencing grade \u22653 anaemia (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001) and thrombocytopenia (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001), respectively. Antiemetic prophylaxis was associated with lower rates of nausea\/vomiting (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Fedratinib exposure was positively associated with spleen volume reduction and TSS responses, without having significant impact on safety. Fedratinib 400\u2009mg once daily is an appropriate dose for patients with MF regardless of ruxolitinib exposure.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bcp.70118","type":"journal-article","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T03:25:59Z","timestamp":1749439559000},"page":"2919-2931","source":"Crossref","is-referenced-by-count":1,"title":["Exposure\u2013response relationship of fedratinib in patients with intermediate\u20102 or high\u2010risk myelofibrosis"],"prefix":"10.1002","volume":"91","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1782-6709","authenticated-orcid":false,"given":"Yizhe","family":"Chen","sequence":"first","affiliation":[{"name":"Translational Medicine and Clinical Pharmacology Bristol Myers Squibb  Princeton NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"Translational Medicine and Clinical Pharmacology Bristol Myers Squibb  Princeton NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongjun","family":"Xue","sequence":"additional","affiliation":[{"name":"Translational Medicine and Clinical Pharmacology Bristol Myers Squibb  Princeton NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Brown","sequence":"additional","affiliation":[{"name":"Global Drug Development Bristol Myers Squibb  Princeton NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Global Drug Development Bristol Myers Squibb  Princeton NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shelonitda","family":"Rose","sequence":"additional","affiliation":[{"name":"Global Drug Development Bristol Myers Squibb  Princeton NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Pilot","sequence":"additional","affiliation":[{"name":"Worldwide Patient Safety Bristol Myers Squibb  Princeton NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gopal","family":"Krishna","sequence":"additional","affiliation":[{"name":"Global Drug Development Bristol Myers Squibb  Princeton NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4264-8927","authenticated-orcid":false,"given":"Ken","family":"Ogasawara","sequence":"additional","affiliation":[{"name":"Translational Medicine and Clinical Pharmacology Bristol Myers Squibb  Princeton NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,6,9]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022017423"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.26857"},{"key":"e_1_2_11_4_1","unstructured":"Bristol Myers Squibb.Inrebic\u00ae (fedratinib) package insert. July2024. Accessed August 2024.https:\/\/packageinserts.bms.com\/pi\/pi_inrebic.pdf"},{"key":"e_1_2_11_5_1","unstructured":"Bristol Myers Squibb.Inrebic\u00ae (fedratinib) summary of product characteristics. May2024. Accessed August 2024.https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/inrebic-epar-product-information_en.pdf"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.17727"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.25777"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2024.2346733"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352\u20103026(24)00212\u20106"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.18207"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102022\u2010156669"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352\u20103026(17)30237\u20105"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352\u20103026(23)00174\u20106"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2017.5818"},{"key":"e_1_2_11_15_1","unstructured":"CTI BioPharma Corp.Vonjo\u00ae (pacritinib) prescribing information. Accessed April 17 2023.https:\/\/www.ctibiopharma.com\/wp-content\/uploads\/2022\/03\/VONJO_PI_02-2022.pdf"},{"key":"e_1_2_11_16_1","unstructured":"GlaxoSmithKline.Ojjaara\u00ae (momelotinib) prescribing information. Accessed April 17 2023.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2023\/216873s000lbl.pdf"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.32.8021"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/bcj.2015.63"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280\u2010019\u201003929\u20109"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.161"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.218"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280\u2010020\u201004121\u20100"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280\u2010020\u201004102\u20103"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12585"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102013\u201003\u2010488098"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2009.01.035"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928\u2010023\u201009850\u20102"},{"key":"e_1_2_11_28_1","first-page":"3431","article-title":"A full model estimation approach for covariate effects: inference based on clinical importance and estimation precision","volume":"6","author":"Gastonguay M","year":"2004","journal-title":"AAPS J"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/psp.2013.7"},{"key":"e_1_2_11_30_1","unstructured":"US Food and Drug Administration.2023.Optimizing the dosage of human prescription drugs and biological products for the treatment of oncologic diseases. Accessed October 14 2024.https:\/\/www.fda.gov\/media\/164555\/download"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201016\u20102842"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2561"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/(sici)1097\u20100258(20000430)19:8<1059::aid\u2010sim412>3.0.co;2\u20100"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2024.2346733"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2020.1845334"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1186\/1756\u20108722\u20106\u201079"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2015.1590"}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bcp.70118","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T07:30:43Z","timestamp":1758871843000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1002\/bcp.70118"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,9]]},"references-count":36,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1002\/bcp.70118"],"URL":"https:\/\/doi.org\/10.1002\/bcp.70118","archive":["Portico"],"relation":{},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"type":"print","value":"0306-5251"},{"type":"electronic","value":"1365-2125"}],"subject":[],"published":{"date-parts":[[2025,6,9]]}}}