{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:07:52Z","timestamp":1790741272813,"version":"4.1.0"},"reference-count":30,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T00:00:00Z","timestamp":1723507200000},"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":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mavacamten is a selective, allosteric, reversible cardiac myosin inhibitor that has been developed for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM). A population pharmacokinetic (PopPK) model was developed to characterize mavacamten pharmacokinetics (PK) and the variation in mavacamten exposure associated with intrinsic and extrinsic factors. Data from 12 clinical studies (phases 1, 2, and 3) were used. Evaluable participants were those who had at least one mavacamten concentration measurement with associated sampling time and dosing information. The base model included key covariates: body weight, cytochrome P450 isozyme 2C19 (CYP2C19) phenotype with respect to PK, and formulation. The final model was generated using stepwise covariate testing and refinement processes. Simulations were performed to evaluate PK: apparent clearance (CL\/F); apparent central and peripheral volumes of distribution; and steady\u2010state average, trough, and maximum concentrations. Overall, 9244 measurable PK observations from 497 participants were included. A two\u2010compartment model structure was selected. After stepwise covariate model building and refinement, additional covariates included were: specified mavacamten dose, omeprazole or esomeprazole administration, health\/disease status, estimated glomerular filtration rate, fed status, and sex. The final PopPK model accurately characterized mavacamten concentrations. At any given dose, CYP2C19 phenotype was the most influential covariate on exposure parameters (e.g., median CL\/F was reduced by 72% in CYP2C19:poor metabolizers compared with the reference participant [CYP2C19:normal metabolizer]). CL\/F was also approximately 16% higher in women than in men but lower in participants receiving concomitant omeprazole or esomeprazole (by 33% and 42%, respectively) than in participants not receiving such concomitant therapy.<\/jats:p>","DOI":"10.1002\/psp4.13197","type":"journal-article","created":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T10:43:55Z","timestamp":1723545835000},"page":"1462-1475","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Characterization of mavacamten pharmacokinetics in patients with hypertrophic cardiomyopathy to inform dose titration"],"prefix":"10.1002","volume":"13","author":[{"given":"Peter","family":"Chang","sequence":"first","affiliation":[{"name":"Certara, Inc.  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\u00a0Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"Salinger","sequence":"additional","affiliation":[{"name":"Certara, Inc.  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6659-3687","authenticated-orcid":false,"given":"Samira","family":"Merali","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New\u00a0Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4398-3865","authenticated-orcid":false,"given":"Neelima","family":"Thanneer","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New\u00a0Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3477-9257","authenticated-orcid":false,"given":"Hyunmoon","family":"Back","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New\u00a0Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie D.","family":"Seroogy","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New\u00a0Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel D.","family":"Gretler","sequence":"additional","affiliation":[{"name":"Daniel Gretler Consulting  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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\u00a0Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1518-5688","authenticated-orcid":false,"given":"Maria","family":"Palmisano","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New\u00a0Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2140-1455","authenticated-orcid":false,"given":"Amit","family":"Roy","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New\u00a0Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,8,13]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(21)01205-8"},{"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":"10.1038\/s41569-022-00682-0"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.106.644682"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1161\/cir.0000000000000937"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehl041"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2022.03.023"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1080\/13696998.2021.1978242"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2009.01.079"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s41687-020-00269-8"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2021.11.021"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(20)31792-x"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2020.03.064"},{"key":"e_1_2_10_15_1","unstructured":"MyoKardia Inc.CAMZYOS\u2122 (mavacamten) full prescribing information.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2022\/214998s000lbl.pdfAccessed February 8 2023."},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1080\/00498254.2018.1495856"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.1151"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.1151"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.1151"},{"key":"e_1_2_10_20_1","unstructured":"MyoKardia Inc.NCT02356289. 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Clinical study to evaluate mavacamten (MYK\u2010461) in adults with symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER\u2010HCM).https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03470545Accessed November 7 2022."},{"key":"e_1_2_10_24_1","unstructured":"MyoKardia Inc.NCT03442764. A phase 2 study of mavacamten in adults with symptomatic non\u2010obstructive hypertrophic cardiomyopathy (nHCM) (MAVERICK\u2010HCM).https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03442764Accessed November 7 2022."},{"key":"e_1_2_10_25_1","unstructured":"Bristol Myers Squibb.NCT03723655. A long\u2010term safety extension study of mavacamten in adults who have completed MAVERICK\u2010HCM or EXPLORER\u2010HCM.https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03723655Accessed November 7 2022."},{"key":"e_1_2_10_26_1","unstructured":"Bristol\u2010Myers Squibb.NCT03496168. 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