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

Abstract

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.

Fig. 1

Mean pulmonary artery pressure at catheterization before and after initiation of ambrisentan therapy. The figure displays the longitudinal change in mean pulmonary artery pressure before and after initiation of ambrisentan therapy. The time of onset of ambrisentan therapy is zero with the number of months before and after ambrisentan therapy on x-axis. a: Transition cases (n = 10). In 7 of 10 patients with cardiac catheterization data before and after ambrisentan therapy, mean pulmonary artery pressure was improved after transition from bosentan therapy. b: Add-on cases (n = 13). In 11 of 13 patients with cardiac catheterization data before and after ambrisentan therapy, mean pulmonary artery pressure was improved after add-on ambrisentan therapy.

Fig. 2

Change in WHO Functional Class between baseline and initiation of ambrisentan therapy. In transition and add-on cases, WHO functional class II or III patients improved to class I or II. WHO; World Health Organization.