Birth Defects Res. 2025 Jul;117(7):e2504. doi: 10.1002/bdr2.2504.ABSTRACTBACKGROUND: Ambrisentan is a selective endothelin-1 receptor antagonist marketed for pulmonary arterial hypertension (PAH) in adults, adolescents, and children above 8 years old.METHOD: A juvenile toxicity study conducted to support clinical studies in patients under 8 years old dosed rats from postnatal days 7 to 62. In subsequent investigative studies, respiratory function was assessed by ventilatory parameters and arterial blood gases, along with other endpoints.RESULTS: Noisy breathing occurred, and brain weight was lower (4%, p < 0.05) without histologic changes at the highest dose (20 mg/kg/day). Respiratory sounds described as clicking noises seemingly synchronous with the breathing cycle were sustained. Hypoxemia and hypercapnia associated with apneic times occurred, suggesting an intermittent physical airway blockade.CONCLUSION: It's postulated that the brain weight decrease was mediated by sustained hypoxemia during a period of rapid brain growth. Improper interaction of rat laryngeal tissues, in close apposition during early postnatal stages, may constitute a sensitive period. Clinical relevance is unknown; palatal/laryngeal maturation timing in healthy children supports up to ~2 years as the period for any potential risk. However, for children with PAH, chronic hypoxemia and/or concomitant conditions associated with developmental delay could hypothetically extend the sensitive age period for potential risk through the third year of life.PMID:40650459 | DOI:10.1002/bdr2.2504