{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T21:57:57Z","timestamp":1790114277690,"version":"4.0.1"},"reference-count":21,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2023,11,4]],"date-time":"2023-11-04T00:00:00Z","timestamp":1699056000000},"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":["Clinical Translational Sci"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Encorafenib is a potent and selective ATP competitive inhibitor of BRAF V600\u2013mutant kinase approved for patients with BRAF\u2010mutant melanoma and colorectal cancer. Encorafenib is mainly metabolized by cytochrome P450 (CYP) 3A4 in\u00a0vitro and may be susceptible to drug\u2013drug interactions when co\u2010administered with CYP3A inhibitors or inducers. The primary objective was to assess the impact of the strong CYP3A inhibitor posaconazole (part 1) and the moderate CYP3A and P\u2010gp inhibitor diltiazem (part 2) on encorafenib pharmacokinetics in healthy volunteers following a single 50\u2010mg dose. A total of 32 participants were enrolled (16 each in parts 1 and 2). The area under the curve extrapolated to infinity (AUC<jats:sub>inf<\/jats:sub>) and maximum plasma concentration (<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>) geometric mean for encorafenib increased by 183% and 68.4%, respectively, when co\u2010administered with posaconazole. Apparent encorafenib clearance decreased from 26.0 to 9.2\u2009L\/h when coadministered with posaconazole, and plasma terminal half\u2010life (<jats:italic>t<\/jats:italic><jats:sub>\u00bd<\/jats:sub>) of encorafenib increased from 4.3 to 7.3\u2009h. The AUC<jats:sub>inf<\/jats:sub> and <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> geometric mean for encorafenib increased by 83.0% and 44.7%, respectively, when co\u2010administered with diltiazem. Similarly, the apparent encorafenib clearance decreased from 29.0 to 16.0\u2009L\/h when co\u2010administered with diltiazem, and plasma <jats:italic>t<\/jats:italic><jats:sub>\u00bd<\/jats:sub> of encorafenib increased from 6.6 to 7.9\u2009h. There were no deaths, serious adverse events (AEs), or patient discontinuations due to AEs in parts 1 or 2. The most frequently reported treatment\u2010related AEs were erythema (<jats:italic>n<\/jats:italic>\u2009=\u200914; 88%) and headache (<jats:italic>n<\/jats:italic>\u2009=\u200911; 69%) in part 1 and headache (<jats:italic>n<\/jats:italic>\u2009=\u20097; 44%) in part 2. The results of this study indicate that co\u2010administration of encorafenib with strong or moderate CYP3A4 inhibitors should be avoided.<\/jats:p>","DOI":"10.1111\/cts.13662","type":"journal-article","created":{"date-parts":[[2023,10,14]],"date-time":"2023-10-14T04:54:26Z","timestamp":1697259266000},"page":"2675-2686","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Impact of posaconazole and diltiazem on pharmacokinetics of encorafenib, a BRAF V600 kinase inhibitor for melanoma and colorectal cancer with BRAF mutations"],"prefix":"10.1111","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6061-1442","authenticated-orcid":false,"given":"Erik","family":"Hahn","sequence":"first","affiliation":[{"name":"Global Product Development Pfizer Inc.  Boulder Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3634-0249","authenticated-orcid":false,"given":"Renae","family":"Chavira","sequence":"additional","affiliation":[{"name":"Global Product Development Pfizer Inc.  Boulder Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4791-8655","authenticated-orcid":false,"given":"Lance","family":"Wollenberg","sequence":"additional","affiliation":[{"name":"Early Clinical Development Pfizer Inc.  Boulder Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Tan","sequence":"additional","affiliation":[{"name":"Global Product Development Pfizer Inc.  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2721-3714","authenticated-orcid":false,"given":"Micaela B.","family":"Reddy","sequence":"additional","affiliation":[{"name":"Early Clinical Development Pfizer Inc.  Boulder Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,11,4]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30142-6"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30497-2"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1908075"},{"key":"e_1_2_11_5_1","unstructured":"European Medicines Agency.Braftovi (encorafenib) summary of product characteristics.2021https:\/\/www.ema.europa.eu\/en\/documents\/product\u2010information\/braftovi\u2010epar\u2010product\u2010information_en.pdf. Accessed 12 April 2021."},{"key":"e_1_2_11_6_1","unstructured":"ClinicalTrials.gov.Pharmacokinetic drug\u2010drug interaction study of encorafenib and binimetinib on probe drugs in patients with BRAF V600\u2010mutant melanoma or other advanced solid tumors.2023https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03864042Accessed 28 February 2023"},{"key":"e_1_2_11_7_1","unstructured":"US Food and Drug Administration.Nofaxil (posaconazole) highlights of prescribing information.2015https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2015\/022003s018s020 0205053s002s004 0205596s001s003lbl.pdfAccessed 12 April 2021."},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2009.02.022"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425255.2012.639360"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1592\/phco.27.6.825"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1185\/03007990802644209"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02931-15"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.32.2.267"},{"key":"e_1_2_11_14_1","first-page":"294","article-title":"Role of CYP3A4 in human hepatic diltiazem N\u2010demethylation: inhibition of CYP3A4 activity by oxidized diltiazem metabolites","volume":"282","author":"Sutton D","year":"1997","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_11_15_1","unstructured":"US Food and Drug Administration.Drug development and drug interactions: table of substrates inhibitors and inducers.2022https:\/\/www.fda.gov\/drugs\/drug\u2010interactions\u2010labeling\/drug\u2010development\u2010and\u2010drug\u2010interactions\u2010table\u2010substrates\u2010inhibitors\u2010and\u2010inducersAccessed 19 January 2023."},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40261-019-00764-x"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12541"},{"key":"e_1_2_11_18_1","unstructured":"US Food and Drug Administration.NOXAFIL (posaconazole) highlights of prescribing information.2021https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2021\/214770s000 205053s012 205596s012lbl.pdfAccessed 19 January 2023."},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270010387141"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdd.748"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.1140"},{"key":"e_1_2_11_22_1","unstructured":"US Food and Drug Administration.Braftovi (encorafenib) prescribing information.2020https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2020\/210496s006lbl.pdf. 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