PMID- 38366267 OWN - NLM STAT- MEDLINE DCOM- 20240423 LR - 20240426 IS - 1432-1076 (Electronic) IS - 0340-6199 (Print) IS - 0340-6199 (Linking) VI - 183 IP - 5 DP - 2024 May TI - Long-term safety and tolerability of ambrisentan treatment for pediatric patients with pulmonary arterial hypertension: An open-label extension study. PG - 2141-2153 LID - 10.1007/s00431-024-05446-1 [doi] AB - This open-label, extension study assessed long-term safety, tolerability, and efficacy of ambrisentan in a pediatric population (age 8- < 18 years) with pulmonary arterial hypertension (PAH). Following completion of a 6-month, randomized study, participants entered the long-term extension at individualized ambrisentan dosages (2.5/5/7.5 or 10 mg/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). Thirty-eight of 41 (93%) randomized study participants entered the extension; 21 (55%) completed (reaching age 18 years). Most participants received concomitant phosphodiesterase-5 inhibitors (n = 25/38, 66%). Median ambrisentan exposure was 3.5 years. Most participants experienced >/= 1 AE (n = 34/38, 89%), and 21 (55%) experienced SAEs, most commonly worsening PAH (n = 3/38, 8%), acute cardiac failure, pneumonia, or anemia (n = 2/38; 5% each); none considered ambrisentan-related. Seven participants (18%) died, with recorded reasons (MedDRA preferred term): cardiac failure (n = 2), PAH (n = 2), COVID-19 (n = 1), acute right ventricular failure (n = 1), and failure to thrive (n = 1); median time to death: 5.2 years. 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: 34.3%), and all (29/29, 100%) had improved or unchanged WHO FC. Conclusion: Long-term weight-based ambrisentan dosing, alone or combined with other PAH therapies in children with PAH aged 8- < 18 years, exhibited tolerability and clinical improvements consistent with prior randomized study results. Trial registration: NCT01342952, April 27, 2011. What is Known: * 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. What is New: * This open-label extension study assessed the long-term use of ambrisentan in pediatric patients (8-<18 years) with PAH, most of whom were also receiving recommended background PAH treatment. * 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. CI - (c) 2024. The Author(s). FAU - Ivy, Dunbar AU - Ivy D AD - Pediatric Cardiology, Children's Hospital Colorado, Aurora, CO, USA. FAU - Beghetti, Maurice AU - Beghetti M AD - Pediatric Cardiology Unit, University Children's Hospital HUG, Pulmonary Hypertension Program HUG, University of Geneva, Geneva, Switzerland. FAU - Juaneda-Simian, Ernesto AU - Juaneda-Simian E AD - Pediatric Cardiology, Department of Cardiology, Hospital de Ninos de la Santisma Trinidad, Cordoba, Argentina. FAU - Ravindranath, Ramiya AU - Ravindranath R AD - Biostatistics (R&D), GSK, Bangalore, India. FAU - Lukas, Mary Ann AU - Lukas MA AUID- ORCID: 0000-0003-0791-5580 AD - Respiratory/Immunology Clinical Research, GSK, 1250 S Collegeville Rd, Collegeville, Philadelphia, PA, 19426, USA. mary.ann.lukas@gsk.com. FAU - Machlitt-Northen, Sandra AU - Machlitt-Northen S AD - Clinical Science, GSK Medicines Research Centre, Stevenage, UK. FAU - Scott, Nicola AU - Scott N AD - Global Safety, GSK, Brentford, Middlesex, UK. FAU - Narita, Jun AU - Narita J AD - Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan. FAU - Berger, Rolf M F AU - Berger RMF AD - Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. LA - eng PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial DEP - 20240216 PL - Germany TA - Eur J Pediatr JT - European journal of pediatrics JID - 7603873 RN - HW6NV07QEC (ambrisentan) RN - 0 (Pyridazines) RN - 0 (Phenylpropionates) RN - 0 (Antihypertensive Agents) SB - IM MH - Humans MH - *Pyridazines/adverse effects/therapeutic use/administration & dosage MH - *Phenylpropionates/administration & dosage/adverse effects/therapeutic use MH - Male MH - Child MH - Female MH - Adolescent MH - Treatment Outcome MH - *Pulmonary Arterial Hypertension/drug therapy MH - Antihypertensive Agents/adverse effects/administration & dosage/therapeutic use MH - Dose-Response Relationship, Drug MH - Walk Test MH - Hypertension, Pulmonary/drug therapy PMC - PMC11035402 OTO - NOTNLM OT - Ambrisentan OT - Endothelin receptor antagonist OT - Open-label extension OT - Pediatric PAH COIS- 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. EDAT- 2024/02/17 12:42 MHDA- 2024/04/23 15:49 PMCR- 2024/02/16 CRDT- 2024/02/17 00:12 PHST- 2023/09/08 00:00 [received] PHST- 2024/01/21 00:00 [accepted] PHST- 2024/01/08 00:00 [revised] PHST- 2024/04/23 15:49 [medline] PHST- 2024/02/17 12:42 [pubmed] PHST- 2024/02/17 00:12 [entrez] PHST- 2024/02/16 00:00 [pmc-release] AID - 10.1007/s00431-024-05446-1 [pii] AID - 5446 [pii] AID - 10.1007/s00431-024-05446-1 [doi] PST - ppublish SO - Eur J Pediatr. 2024 May;183(5):2141-2153. doi: 10.1007/s00431-024-05446-1. Epub 2024 Feb 16.