{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T04:14:54Z","timestamp":1772856894528,"version":"3.50.1"},"reference-count":27,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2017,4,5]],"date-time":"2017-04-05T00:00:00Z","timestamp":1491350400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100005646","name":"Actelion Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005646","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2017,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Macitentan is a worldwide approved dual endothelin receptor antagonist that has demonstrated efficacy in the treatment of pulmonary arterial hypertension (PAH) in a phase 3 clinical trial, SERAPHIN, at a dose of 10\u00a0mg once daily. During this trial, trough plasma concentrations (C<jats:sub>trough<\/jats:sub>) of macitentan and its active metabolite,\u00a0\u00a0ACT\u2010132577,\u00a0\u00a0were obtained at steady state in 242 patients, indicating that mean C<jats:sub>trough<\/jats:sub> of both analytes was about 2\u2010fold higher in PAH patients than in healthy subjects. To further investigate the pharmacokinetics (PK) of macitentan and its active metabolite, ACT\u2010132577,\u00a0\u00a0a 24\u2010hour PK profile was recorded at steady state in 20 PAH patients in the open\u2010label extension of SERAPHIN.\u00a0\u00a0A cross\u2010study comparison showed that although C<jats:sub>trough<\/jats:sub> in PAH patients is higher when compared with a historical reference group of healthy subjects, with geometric mean ratios of 1.45 and 1.36 for macitentan and ACT\u2010132577, respectively, this does not translate to a significant difference in exposure expressed as maximum plasma concentration (C<jats:sub>max<\/jats:sub>) or area under the plasma concentration\u2013time curve over a dosing interval (AUC<jats:sub>\u03c4<\/jats:sub>). Geometric mean ratios for C<jats:sub>max<\/jats:sub> and AUC<jats:sub>\u03c4<\/jats:sub> were 1.08 and 1.22, respectively, for macitentan and 1.24 and 1.31, respectively, for ACT\u2010132577. Therefore, overall exposure at steady state to macitentan and ACT\u2010132577 in PAH patients is considered similar to that in healthy subjects.<\/jats:p>","DOI":"10.1002\/jcph.888","type":"journal-article","created":{"date-parts":[[2017,4,5]],"date-time":"2017-04-05T19:53:44Z","timestamp":1491422024000},"page":"997-1004","source":"Crossref","is-referenced-by-count":6,"title":["Pharmacokinetics of Macitentan in Patients With Pulmonary Arterial Hypertension and Comparison With Healthy Subjects"],"prefix":"10.1002","volume":"57","author":[{"given":"Milena","family":"Issac","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology Actelion Pharmaceuticals Ltd  Allschwil Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jasper","family":"Dingemanse","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology Actelion Pharmaceuticals Ltd  Allschwil Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia N.","family":"Sidharta","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology Actelion Pharmaceuticals Ltd  Allschwil Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,4,5]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0029-1233306"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1586\/erc.10.137"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehp297"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.108.142976"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-015-0322-y"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40264-015-0275-y"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1213917"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1517\/14740338.2014.859674"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.114.214106"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00364-2015"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1177\/1753465814530182"},{"key":"e_1_2_9_13_1","unstructured":"Package Insert Macitentan FDA.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2013\/204410s000lbl.pdf. Accessed July 2016.\u00a0"},{"key":"e_1_2_9_14_1","unstructured":"SmPC macitentan EMA.http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/EPAR_-_Product_Information\/human\/002697\/WC500160899.pdf. Accessed August 2016.\u00a0"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.152"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-011-1043-2"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1159\/000351704"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-015-0255-5"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.639"},{"issue":"1","key":"e_1_2_9_20_1","first-page":"29","article-title":"Pharmacokinetic \/ pharmacodynamic analyses in SERAPHIN, a randomized, controlled study of macitentan in patients with pulmonary arterial hypertension","volume":"2","author":"Zisowsky J SP","year":"2013","journal-title":"Clin Pharmacol Drug Dev"},{"key":"e_1_2_9_21_1","unstructured":"Assessment report Opsumit (INN: Macitentan)2013.http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/EPAR_-_Public_assessment_report\/human\/002697\/WC500160900.pdf. Accessed October 2016.\u00a0"},{"key":"e_1_2_9_22_1","unstructured":"NCT00667823.Clinical study to assess the long\u2010term safety and tolerability of ACT\u2010064992 in patients with symptomatic pulmonary arterial hypertension (SERAPHIN OL). Clinical trials 2013.https:\/\/clinicaltrials.gov\/ct2\/show\/NCT00667823. Accessed October 2016."},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2009.09.005"},{"key":"e_1_2_9_24_1","unstructured":"Administration FaD.Statistical approaches to test bioequivalence. 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