Brain Weight Effect of Ambrisentan in Juvenile Rat Toxicity Studies Associated With Breathing Sounds, Apnea, and Sustained Hypoxemia

Background

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.