{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T15:03:24Z","timestamp":1793113404093,"version":"4.5.0"},"reference-count":45,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Cardiovasc Pharmacol Ther"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Aprocitentan, is an orally active, once-daily administered, dual endothelin receptor antagonist that was recently approved for the treatment of hypertension in combination with other antihypertensive drugs, to lower blood pressure in adult patients who are not adequately controlled on other drugs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The potential of aprocitentan to affect the QT interval was investigated in this thorough QT\/QTc study that was performed as a multiple-dose, randomized, double-blind, placebo- and moxifloxacin-controlled (open-label), crossover study in healthy male and female subjects. Concentration-QT modeling, using a linear mixed-effects model, was performed on data extracted from continuous Holter electrocardiogram recordings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Of the 48 subjects enrolled in the study, 32 subjects completed study treatment. The main reasons for stopping study treatment were the occurrence of adverse events and withdrawal of consent. The dosing regimen of 25 mg aprocitentan o.d. (the highest approved therapeutic dose in the European Union; C\n                      <jats:sub>max<\/jats:sub>\n                      \u2009=\u20093.68 \u00b5g\/mL) was safe and well tolerated; the supratherapeutic dosing regimen of 100 mg aprocitentan o.d. showed limited tolerability. Results indicated that \u0394\u0394QTcF increased with increasing aprocitentan concentrations. The predicted upper bound of the 2-sided 90% \u0394\u0394QTcF confidence interval exceeded the 10 ms threshold of regulatory concern at 16.10 \u00b5g\/mL, which was close to the geometric mean maximum concentration (ie, 16.77 \u00b5g\/mL) obtained with a 100 mg supratherapeutic dose.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>At the highest therapeutic dose of 25 mg, there was no clinically significant prolongation of QTc. The risk of QT prolongation with therapeutic doses of aprocitentan is considered low.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/10742484251351135","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T15:42:58Z","timestamp":1757691778000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinical Evaluation of QTc Interval Prolongation With the Dual Endothelin Receptor Antagonist Aprocitentan"],"prefix":"10.1177","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7581-4525","authenticated-orcid":false,"given":"P.N.","family":"Sidharta","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0813-4463","authenticated-orcid":false,"given":"J.M.","family":"Brussee","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Schultz","sequence":"additional","affiliation":[{"name":"CRS Clinical Research Services Mannheim GmbH, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Wierdak","sequence":"additional","affiliation":[{"name":"CRS Clinical Research Services Mannheim GmbH, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Dingemanse","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,9,12]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61728-0"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61766-8"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYP.0000000000000084"},{"issue":"7884","key":"e_1_3_3_5_2","article-title":"Resistant hypertension","volume":"345","author":"Myat A","year":"2012","unstructured":"Myat A, Redwood SR, Qureshi AC, Spertus JA, Williams B. 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