{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T14:21:34Z","timestamp":1789741294254,"version":"4.0.1"},"reference-count":20,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,8,6]],"date-time":"2023-08-06T00:00:00Z","timestamp":1691280000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:p>Mavacamten is a first\u2010in\u2010class, oral, selective, allosteric, reversible cardiac myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic New York Heart Association functional class II\u2013III obstructive hypertrophic cardiomyopathy. Mavacamten is metabolized in the liver, predominantly via cytochrome P450 (CYP) enzymes CYP2C19 (74%), CYP3A4 (18%), and CYP2C9 (8%). A physiologically\u2010based pharmacokinetic (PBPK) model was developed using Simcyp version 19 (Certara, Princeton, NJ). Following model verification, the PBPK model was used to explore the effects of strong CYP3A4 and CYP2C19 inducers, and strong, moderate, and weak CYP2C19 and CYP3A4 inhibitors on mavacamten pharmacokinetics (PK) in a healthy population, with the effect of CYP2C19 phenotype predicted for poor, intermediate, normal, and ultrarapid metabolizers. The PBPK model met the acceptance criteria for all verification simulations (&gt;\u200980% of model\u2010predicted PK parameters within 2\u2010fold of those observed clinically). A weak induction effect was predicted when mavacamten was administered with a strong CYP3A4 inducer in poor metabolizers. Moderate reductions in mavacamten exposure were predicted with a strong CYP2C19\/CYP3A4 inducer in all CYP2C19 phenotypes. Except for the effect of strong CYP2C19 inhibitors on ultrarapid metabolizers, steady\u2010state area under plasma concentration\u2013time curve and maximum plasma concentration values were weakly affected (&lt;\u20092\u2010fold) or not affected (&lt;\u20091.25\u2010fold), regardless of CYP2C19 phenotype. In conclusion, a fit\u2010for\u2010purpose PBPK model was developed and verified, which accurately predicted the available clinical data and was used to simulate the potential impact of CYP induction and inhibition on mavacamten PKs, stratified by CYP2C19 phenotype.<\/jats:p>","DOI":"10.1002\/cpt.3005","type":"journal-article","created":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T16:57:50Z","timestamp":1689785870000},"page":"922-932","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Physiologically Based Pharmacokinetic Modeling and Simulation of Mavacamten Exposure with Drug\u2013Drug Interactions from CYP Inducers and Inhibitors by CYP2C19 Phenotype"],"prefix":"10.1111","volume":"114","author":[{"given":"Manting","family":"Chiang","sequence":"first","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7255-8500","authenticated-orcid":false,"given":"Caroline","family":"Sychterz","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9055-0123","authenticated-orcid":false,"given":"Vidya","family":"Perera","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samira","family":"Merali","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Palmisano","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian E.","family":"Templeton","sequence":"additional","affiliation":[{"name":"Simcyp Division Certara UK Ltd.  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Gaohua","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,8,6]]},"reference":[{"key":"e_1_2_9_1_1","first-page":"e558","article-title":"2020 AHA\/ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy: a report of the American College of Cardiology\/American Heart Association joint committee on clinical practice guidelines","volume":"142","author":"Ommen S.R.","year":"2020","journal-title":"Circulation"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehu284"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1710575"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hfc.2017.12.004"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.1715"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)31792-X"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00763-7"},{"key":"e_1_2_9_8_1","unstructured":"Full prescribing information [mavacamten] (CAMZYOS\u2122)<https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2022\/214998s000lbl.pdf>. (2022) [cited January 17 2023]."},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1080\/00498254.2018.1495856"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-022-01739-7"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfq374"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.2298"},{"key":"e_1_2_9_13_1","unstructured":"ClinicalTrials.govSingle ascending dose study of MYK\u2010461 in healthy volunteers<https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02356289>. (2015) [cited January 17 2023]."},{"key":"e_1_2_9_14_1","unstructured":"ClinicalTrials.govSafety tolerability pharmacokinetics and pharmacodynamics of multiple ascending oral doses of MYK\u2010461 in healthy volunteers<https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02480296>. (2017) [cited January 17 2023]."},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.37"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1013"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.33"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.114.058099"},{"issue":"1","key":"e_1_2_9_19_1","first-page":"S160","article-title":"Application of PBPK modeling and simulation for regulatory decision making and its impact on US prescribing information: an update on the 2018\u20132019 submissions to the US FDA's office of clinical pharmacology","volume":"60","author":"Zhang X.","year":"2020","journal-title":"J. Clin. Pharmacol."},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40495-020-00212-x"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.3005","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,2]],"date-time":"2024-01-02T04:35:27Z","timestamp":1704170127000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.3005"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,6]]},"references-count":20,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,10]]}},"alternative-id":["10.1002\/cpt.3005"],"URL":"https:\/\/doi.org\/10.1002\/cpt.3005","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,6]]},"assertion":[{"value":"2023-04-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-07-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-06","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}