{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T22:27:57Z","timestamp":1787351277416,"version":"build-2736575974"},"reference-count":15,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2024,2,16]],"date-time":"2024-02-16T00:00:00Z","timestamp":1708041600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,2,16]],"date-time":"2024-02-16T00:00:00Z","timestamp":1708041600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Pediatr"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>This open-label, extension study assessed long-term safety, tolerability, and efficacy of ambrisentan in a pediatric population (age 8\u2013\u2009&lt;\u200918\u00a0years) with pulmonary arterial hypertension (PAH).\u00a0Following completion of a 6-month, randomized study, participants entered the long-term extension at individualized ambrisentan dosages (2.5\/5\/7.5 or 10\u00a0mg\/day). Safety assessments included adverse events (AEs), AEs of special interest, and serious AEs (SAEs); efficacy outcomes included 6-min walking distance (6MWD) and World Health Organization functional class (WHO FC).\u00a0Thirty-eight of 41 (93%) randomized study participants entered the extension; 21 (55%) completed (reaching age 18\u00a0years). Most participants received concomitant phosphodiesterase-5 inhibitors (<jats:italic>n<\/jats:italic>\u2009=\u200925\/38, 66%). Median ambrisentan exposure was 3.5\u00a0years. Most participants experienced\u2009\u2265\u20091 AE (<jats:italic>n<\/jats:italic>\u2009=\u200934\/38, 89%), and 21 (55%) experienced SAEs, most commonly worsening PAH (<jats:italic>n<\/jats:italic>\u2009=\u20093\/38, 8%), acute cardiac failure, pneumonia, or anemia (<jats:italic>n<\/jats:italic>\u2009=\u20092\/38; 5% each); none considered ambrisentan-related. Seven participants (18%) died, with recorded reasons (MedDRA preferred term): cardiac failure (<jats:italic>n<\/jats:italic>\u2009=\u20092), PAH (<jats:italic>n<\/jats:italic>\u2009=\u20092), COVID-19 (<jats:italic>n<\/jats:italic>\u2009=\u20091), acute right ventricular failure (<jats:italic>n<\/jats:italic>\u2009=\u20091), and failure to thrive (<jats:italic>n<\/jats:italic>\u2009=\u20091); median time to death: 5.2\u00a0years. Anemia and hepatotoxicity AEs were generally mild to moderate and did not require ambrisentan dose adjustment. Assessed at study end in 29 participants (76%), mean 6MWD improved by 17% (standard deviation:\u00a034.3%), and all (29\/29, 100%) had improved or unchanged WHO FC.<\/jats:p><jats:p>   \u00a0 \u00a0<jats:italic>Conclusion<\/jats:italic>:\u00a0Long-term weight-based ambrisentan dosing, alone or combined with other PAH therapies in children with PAH aged 8\u2013\u2009&lt;\u200918\u00a0years, exhibited tolerability and clinical improvements consistent with prior randomized study results.<\/jats:p><jats:p>   \u00a0 \u00a0<jats:italic>Trial registration<\/jats:italic>:\u00a0NCT01342952, April 27, 2011.\n<jats:table-wrap><jats:table><jats:tbody>\n                    <jats:tr>\n                      <jats:td colspan=\"2\"><jats:bold>What is Known:<\/jats:bold><jats:italic>\u2022<\/jats:italic><jats:italic>The endothelin receptor antagonist, ambrisentan, is indicated for treatment of pulmonary arterial hypertension (PAH). Previous studies have shown similar efficacy and tolerability in pediatric patients as in adults.<\/jats:italic><\/jats:td>\n                    <\/jats:tr>\n                    <jats:tr>\n                      <jats:td colspan=\"2\"><jats:bold>What is New:<\/jats:bold><jats:italic>\u2022\u00a0This open-label extension study assessed the long-term use of ambrisentan in pediatric patients (8\u2013&lt;18 years) with PAH, most of whom were also receiving recommended background PAH treatment. <\/jats:italic><jats:italic>\u2022\u00a0<\/jats:italic><jats:italic>Weight-based dosing of ambrisentan, given alone or in combination with other PAH therapies, was well tolerated with clinical improvements consistent with prior randomized study results<\/jats:italic><jats:italic>.<\/jats:italic><\/jats:td>\n                    <\/jats:tr>\n                  <\/jats:tbody><\/jats:table><\/jats:table-wrap><\/jats:p>","DOI":"10.1007\/s00431-024-05446-1","type":"journal-article","created":{"date-parts":[[2024,2,16]],"date-time":"2024-02-16T18:02:16Z","timestamp":1708106536000},"page":"2141-2153","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Long-term safety and tolerability of ambrisentan treatment for pediatric patients with pulmonary arterial hypertension: An open-label extension study"],"prefix":"10.1007","volume":"183","author":[{"given":"Dunbar","family":"Ivy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurice","family":"Beghetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto","family":"Juaneda-Simian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramiya","family":"Ravindranath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0791-5580","authenticated-orcid":false,"given":"Mary Ann","family":"Lukas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Machlitt-Northen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Narita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf M. 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The protocol was pre-approved by relevant national, regional, or investigational center ethics committees or institutional review boards.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Written informed consent was obtained from all participants or their parents, as applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"The University of Colorado contracts with GSK, Bayer, Janssen and Merck for DI to be a consultant. MB reports remunerations for lectures and\/or consultancy from Actelion\/Janssen, Acceleron\/Merck, AOP, Bayer, Gossamer, Altavant, Eli Lilly and Company, Occlutech, GSK, and MSD. EJ-S has received funding from GSK. RR, MAL, SM-N, and NS are employees of GSK and hold stock and shares in GSK Group of Companies. JN has no disclosures to report. RMFB has participated in advisory boards and steering committees for GSK, Ely Lilly, MSD, and Janssen through the University Medical Center Groningen.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}