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The phase III EXPLORER\u2010HCM (NCT03470545) study used a dose\u2010titration scheme based on mavacamten exposure and echocardiographic assessment of Valsalva left ventricular outflow tract gradient (VLVOTg) and left ventricular ejection fraction (LVEF). Using population pharmacokinetic\/exposure\u2010response modeling and simulations of virtual patients, this in silico study evaluated alternative dose\u2010titration regimens for mavacamten, including regimens that were guided by echocardiographic measures only. Mavacamten exposure\u2010response models for VLVOTg (efficacy) and LVEF (safety) were developed using patient data from five clinical studies and characterized using nonlinear mixed\u2010effects models. Simulations of five echocardiography\u2010guided regimens were performed in virtual cohorts constructed based on either expected or equal population distributions of cytochrome P450 2C19 (CYP2C19) metabolizer phenotypes. Each regimen aimed to maximize the proportions of patients who achieved a VLVOTg below 30\u2009mm Hg while maintaining LVEF above 50% over 40\u2009weeks and 104\u2009weeks, respectively. The exposure\u2010response models successfully characterized mavacamten efficacy and safety parameters. Overall, the simulated regimen with the optimal benefit\u2013risk profile across CYP2C19 phenotypes had steps for down\u2010titration at weeks 4 and 8 (for VLVOTg &lt;20\u2009mm Hg), and up\u2010titration at week 12 (for VLVOTg \u226530\u2009mm Hg and LVEF \u226555%), and every 12\u2009weeks thereafter. This simulation\u2010optimized regimen is recommended in the mavacamten US prescribing information.<\/jats:p>","DOI":"10.1002\/psp4.13138","type":"journal-article","created":{"date-parts":[[2024,5,2]],"date-time":"2024-05-02T12:23:07Z","timestamp":1714652587000},"page":"1448-1461","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Recommendation of mavacamten posology by model\u2010based analyses in adults with obstructive hypertrophic cardiomyopathy"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6659-3687","authenticated-orcid":false,"given":"Samira","family":"Merali","sequence":"first","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David H.","family":"Salinger","sequence":"additional","affiliation":[{"name":"Certara, Inc.  Princeton New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1518-5688","authenticated-orcid":false,"given":"Maria","family":"Palmisano","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1912-1710","authenticated-orcid":false,"given":"Amy J.","family":"Sehnert","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4398-3865","authenticated-orcid":false,"given":"Neelima","family":"Thanneer","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3477-9257","authenticated-orcid":false,"given":"Hyunmoon","family":"Back","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie D.","family":"Seroogy","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel D.","family":"Gretler","sequence":"additional","affiliation":[{"name":"Daniel Gretler Consulting  San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2140-1455","authenticated-orcid":false,"given":"Amit","family":"Roy","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,5,2]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000937"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hfc.2017.12.004"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12551-017-0274-6"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehac544.1747"},{"key":"e_1_2_10_6_1","volume-title":"package insert","author":"CAMZYOS (mavacamten)","year":"2022"},{"key":"e_1_2_10_7_1","volume-title":"Australian Product Information","author":"CAMZYOS (mavacamten)","year":"2022"},{"key":"e_1_2_10_8_1","volume-title":"Brazilian bula profissional","author":"CAMZYOS (mavacamteno)","year":"2023"},{"key":"e_1_2_10_9_1","volume-title":"Canadian Product Monograph","author":"CAMZYOS (mavacamten)","year":"2022"},{"key":"e_1_2_10_10_1","volume-title":"Professional Information, Swissmedic","author":"CAMZYOS\u00ae (mavacamtenum)","year":"2023"},{"key":"e_1_2_10_11_1","volume-title":"European Summary of Product Characteristics","author":"CAMZYOS (mavacamten)","year":"2023"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1809540115"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1080\/00498254.2018.1495856"},{"key":"e_1_2_10_14_1","unstructured":"PereraV GretlerDD SeroogyJD ChiangM PalmisanoM FloreaV.Pharmacokinetic Drug\u2010Drug Interaction Study of Mavacamten with Verapamil in Healthy Subjects. Poster presented at: American College of Clinical Pharmacology (ACCP) Annual Meeting North Bethesda MD USA. September 25\u201327 2022."},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1691\/ph.2018.8689"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.7326\/m18-3016"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)31792-X"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2023.09.028"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1161\/circ.140.suppl_1.13962"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2020.03.064"},{"key":"e_1_2_10_21_1","unstructured":"Centre for Drug Evaluation and Research.Clinical pharmacology review. Mavacamten.2022. Accessed February 26 2024.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2022\/214998Orig1s000ClinPharmR.pdf"},{"key":"e_1_2_10_22_1","unstructured":"European Medicines Agency.Assessment report. 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