{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T16:45:13Z","timestamp":1787589913726,"version":"build-2736575974"},"reference-count":25,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T00:00:00Z","timestamp":1754956800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T00:00:00Z","timestamp":1754956800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mavacamten, a cardiac myosin inhibitor, is primarily metabolized by the cytochrome P450 (CYP) enzymes CYP2C19 and CYP3A4, and coadministration with strong CYP3A4 or CYP2C19 inhibitors was contraindicated in patients with obstructive hypertrophic cardiomyopathy (HCM) in the US Prescribing Information. This study assessed the safety and efficacy of modifying mavacamten posology to accommodate coadministration with strong CYP3A4 and strong\/moderate CYP2C19 inhibitors. Simulations of 5000 virtual patients with obstructive HCM with an equal distribution of CYP2C19 metabolizer phenotypes were performed using population pharmacokinetic and exposure\u2013response modeling approaches. A reference posology and variations thereof were simulated to evaluate long\u2010term (chronic) and short\u2010term (1\u2010week) coadministration with CYP3A4 or CYP2C19 inhibitors. Proportions of patients with left ventricular ejection fraction (LVEF) &lt;50% and Valsalva left ventricular outflow tract gradient (VLVOTg) &lt;30\u00a0mm Hg were evaluated to assess safety and efficacy, respectively. Compared with the reference posology, a modified posology, which used a 2.5\u2010mg starting dose with coadministration being stopped if LVEF was &lt;50% at any time when receiving 2.5 mg, resulted in a similar peak proportion of CYP2C19 poor metabolizers and CYP2C19 ultrarapid metabolizers with LVEF &lt;50% when initiating mavacamten with a CYP3A4 or CYP2C19 inhibitor, respectively. Achievement of optimal efficacy was delayed in some patients owing to dose reduction. Initiation of CYP3A4 or CYP2C19 inhibitor treatment in patients receiving stable mavacamten therapy was accommodated through mavacamten dose reduction by one level. Interruption of mavacamten during short\u2010term administration of inhibitors transiently increased VLVOTg for the duration of interruption, with no effect on LVEF.<\/jats:p>","DOI":"10.1002\/jcph.70072","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T02:58:51Z","timestamp":1755053931000},"page":"1802-1814","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Exposure\u2013Response Modeling and Simulation to Identify Optimal Mavacamten Posology When Coadministered with CYP3A4 and CYP2C19 Inhibitors in Patients with Obstructive HCM"],"prefix":"10.1002","volume":"65","author":[{"given":"Samira","family":"Merali","sequence":"first","affiliation":[{"name":"Bristol\u2010Myers Squibb  Princeton NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haden","family":"Bunn","sequence":"additional","affiliation":[{"name":"Pumas\u2010AI Inc., Baltimore  MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Sychterz","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb  Princeton NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manting","family":"Chiang","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb  Princeton NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shilpa","family":"Puli","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb  Princeton NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy J.","family":"Sehnert","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb  Princeton NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bindu","family":"Murthy","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb  Princeton NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8348-4295","authenticated-orcid":false,"given":"Joga","family":"Gobburu","sequence":"additional","affiliation":[{"name":"Pumas\u2010AI Inc., Baltimore  MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,12]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hfc.2017.12.004"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.1715"},{"key":"e_1_2_11_4_1","first-page":"e558","article-title":"2020 AHA\/ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy","volume":"142","author":"Ommen SR","year":"2020","journal-title":"Circulation"},{"key":"e_1_2_11_5_1","unstructured":"Bristol\u2010Myers Squibb Company.CAMZYOS (mavacamten). US prescribing information. Accessed April 23 2025.https:\/\/packageinserts.bms.com\/pi\/pi_camzyos.pdf"},{"key":"e_1_2_11_6_1","unstructured":"Bristol\u2010Myers Squibb Australia Pty Ltd.CAMZYOS (mavacamten). Australian product information. Accessed November 26 2024.https:\/\/www.tga.gov.au\/sites\/default\/files\/2023\u201007\/auspar\u2010camzyos\u2010230703\u2010pi.pdf"},{"key":"e_1_2_11_7_1","unstructured":"Bristol\u2010Myers Squibb Farmac\u00eautica LTDA.CAMZYOS (mavacanteno). Brazilian bula profissional. Accessed November 26 2024.https:\/\/www.bms.com\/assets\/bms\/brazil\/documents\/Camzyos_Bula_Profissional.pdf"},{"key":"e_1_2_11_8_1","unstructured":"Bristol\u2010Myers Squibb Canada.CAMZYOS (mavacamten). Canadian product monograph. Accessed November 26 2024.https:\/\/www.bms.com\/assets\/bms\/ca\/documents\/productmonograph\/CAMZYOS_EN_PM.pdf"},{"key":"e_1_2_11_9_1","unstructured":"Bristol\u2010Myers SquibbSA.CAMZYOS (mavacamtenum). Professional information Swissmedic. 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