Clinical safety, pharmacokinetics, and efficacy of ambrisentan therapy in children with pulmonary arterial hypertension

Abstract

Summary Recent trials in adult PAH revealed the efficacy of ambrisentan. However, in children with PAH, the clinical safety and pharmacokinetics of ambrisentan has not been well studied. Our aim was to investigate the clinical safety, pharmacokinetics, tolerability, and efficacy of endothelin receptor antagonist therapy with ambrisentan in children with pulmonary arterial hypertension (PAH). This retrospective cohort study provides clinical data from pediatric patients with PAH receiving ambrisentan as add-on therapy or transition from bosentan. Safety included evaluation of adverse events including aminotransferase abnormalities. The clinical impact was evaluated by improvement from baseline in clinical variables. A total of 38 pediatric patients with PAH received ambrisentan. Fifteen of 38 patients were switched from bosentan to ambrisentan. The remaining 23 children were treated with ambrisentan as an add-on therapy due to disease progression. In both transition and add-on cases, mean pulmonary artery pressure significantly improved (transition; 55 ± 18 vs. 45 ± 20 mmHg, n = 13, P = 0.04, add-on; 52 ± 17 vs. 45 ± 19 mmHg, n = 13, P = 0.03) during the follow-up. World Health Organization functional class improved in 31% of patients, but one patient required an atrial septostomy due to disease progression during the follow-up period (median, range; 20, 4–44 months). Five patients (13%) discontinued ambrisentan due to severe headache, lack of clinical efficacy, or near syncope. Ten patients (26%) had side effects associated with ambrisentan treatment, including nasal congestion, headache, and flushing. However, no patients had aminotransferase abnormalities and there were no deaths after initiation of ambrisentan during follow-up. Pharmacokinetics were evaluated in sixteen children treated with ambrisentan from 2.5 mg to 10.0 mg; the mean peak plasma concentration was 738 ± 452 ng/ml, mean time to peak plasma concentration was 3.2 ± 2.1 hours, and mean area under the curve plasma concentration was 6657 ± 4246 ng·hour/ml. In conclusion, initial experience with ambrisentan in children suggests that treatment is safe with similar pharmacokinetics to those in adults and may improve PAH in some children.

Idiopathic Pulmonary Arterial Hypertension in Children: A Review

“…The most common side effects are nasal congestion and headaches. Ambrisentan has shown improvement of WHO-FC and hemodynamics in children with PAH, and some children can be safely switched from bosentan to ambrisentan [138].…”

Can Pulmonary Vasodilator Therapy Expand the Operative Indications for Congenital Heart Disease?

“…6,7) Pulmonary vasodilator therapy improves outcomes in patients with idiopathic PAH, and has also been reported to be effective in patients with other types of PAH. [8][9][10][11][12][13] This therapy may reduce pulmonary vascular resistance (Rp) in patients who were previously thought to have irreversible pulmonary vascular disease.…”

“…6,42) These vasodilators have been shown to improve functional status and survival in patients with idiopathic PAH. [6][7][8][9][10][11][12][13] Pulmonary vasodilator therapy is now being used to treat PAH in patients with CHD, including those with Eisenmenger syndrome. Many reports have indicated that the endothelin receptor antagonist bosentan is effective for improving clinical outcomes and exercise capacity in patients with Eisenmenger syndrome.…”

Therapeutic Options for Childhood Pulmonary Hypertension

“…Ambrisentan, a selective ET A receptor blocker (which can be administered once a day and has been reported with no hepatotoxicity) was found to be efficacious in children with an acceptable safety profile. 24 Macitentan is a tissue-specific ERA that is now FDA approved for use in adult PAH, and studies in pediatric patients are ongoing.…”