{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T03:07:56Z","timestamp":1778728076999,"version":"3.51.4"},"reference-count":10,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2026,5]]},"abstract":"ABSTRACT<\/jats:title>\n \n In the phase 3 study SEQUOIA\u2010HCM (NCT05186818), aficamten, a next\u2010in\u2010class cardiac myosin inhibitor, was safe and efficacious in participants with obstructive hypertrophic cardiomyopathy (oHCM). Using pharmacokinetics\/pharmacodynamics (PKPD) modeling, we quantified the relationship between aficamten exposure and cardiodynamic measures of safety (left ventricular ejection fraction [LVEF]) and efficacy (post\u2010Valsalva left ventricular outflow tract gradient [LVOT\u2010G]), and used Clinical Trial Simulations (CTS) to predict cardiodynamics for a flexible dose regimen in a post\u2010approval setting. PKPD relationships between aficamten average concentration over 24\u2009h (C\n avg,24<\/jats:sub>\n ) and LVEF or LVOT\u2010G were well quantified. Within\u2010subject variability for LVEF was low (CV\u2009=\u20097.6%), indicating that prior LVEF readings are highly predictive of future readings during stable therapy. A ~2% decrease in LVEF is expected per 100\u2009ng\/mL increase in C\n avg,24<\/jats:sub>\n . LVOT\u2010G slope was ~10\u2010fold steeper vs. LVEF, suggesting a relatively large therapeutic window. The commercial regimen allows for individualized flexible echocardiography\u2010based dose titration (every 2\u20138\u2009weeks) from 5 to 20\u2009mg once daily and flexible maintenance dose monitoring. CTS demonstrated minimal differences in population progression of LVOT\u2010G\u2009<\u200930\u2009mmHg and LVEF <\u200950% between evaluated dose\u2010titration frequencies (every 2, 4, 6, or 8\u2009weeks) over the first 6\u2009months of treatment, supporting a 2\u20138\u2009week window for dose titration. With maintenance doses, the probability of maintaining LVOT\u2010G\u2009<\u200930\u2009mmHg (~60%) was high and the probability of occurrences of LVEF <\u200950% (~3%) was low. Therefore, this regimen should maintain safe and efficacious cardiodynamics while increasing convenience and access for patients with oHCM.\n <\/jats:p>","DOI":"10.1002\/psp4.70237","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T14:35:04Z","timestamp":1778250904000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Towards a Quantitative Understanding of Aficamten Clinical Pharmacology: Pharmacokinetic\u2010Cardiodynamic Modeling to Support Safety and Efficacy"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9353-9139","authenticated-orcid":false,"given":"Justin D.","family":"Lutz","sequence":"first","affiliation":[{"name":"Clinical Pharmacology, Cytokinetics South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Russ","family":"Wada","sequence":"additional","affiliation":[{"name":"QuanTx Consulting Mountain View California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9182-275X","authenticated-orcid":false,"given":"Daniel L.","family":"Jacoby","sequence":"additional","affiliation":[{"name":"Clinical Research, Cytokinetics South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2189-1474","authenticated-orcid":false,"given":"Stephen B.","family":"Heitner","sequence":"additional","affiliation":[{"name":"Clinical Research, Cytokinetics South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5469-1287","authenticated-orcid":false,"given":"Stuart","family":"Kupfer","sequence":"additional","affiliation":[{"name":"Clinical Research, Cytokinetics South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4516-6691","authenticated-orcid":false,"given":"Polina","family":"German","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, Cytokinetics South San Francisco California USA"},{"name":"Latigo Biotherapeutics Thousand Oaks California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44161\u2010024\u201000505\u20100"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.124.035993"},{"key":"e_1_2_10_4_1","unstructured":"\u201cCAMZYOS (mavacamten) Prescribing Information. Bristol Myers Squibb \u201d (2024) https:\/\/packageinserts.bms.com\/pi\/pi_camzyos.pdf."},{"key":"e_1_2_10_5_1","volume-title":"Drug\u2010Drug Interaction Study to Evaluate the Effect of Cytochrome P450 2C9, 2C19 and 2D6 Inhibition on the Pharmacokinetics of Aficamten in Healthy Participants","author":"Maharao N.","year":"2024"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.70099"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2023.10.004"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2401424"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2022.10.020"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.echo.2018.01.022"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2022.04.008"}],"container-title":["CPT: Pharmacometrics & Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.70237","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/psp4.70237","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.70237","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T02:17:52Z","timestamp":1778725072000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.70237"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5]]},"references-count":10,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["10.1002\/psp4.70237"],"URL":"https:\/\/doi.org\/10.1002\/psp4.70237","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5]]},"assertion":[{"value":"2025-10-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70237"}}