Bosentan: in pediatric patients with pulmonary arterial hypertension

Abstract

Bosentan is a dual endothelin-1 (ET-1) receptor antagonist that has affinity for ET-1 receptors A and B. In the EU, oral bosentan (Tracleer) is indicated to improve exercise capacity and symptoms in patients with pulmonary arterial hypertension (PAH) of WHO functional class III; benefits have also been seen in patients with WHO functional class II PAH. Bosentan is available as film-coated tablets, and a new dispersible formulation of bosentan has also recently been approved in the EU for the treatment of PAH in children aged > or =2 years. A noncomparative, multicenter, phase III trial (FUTURE-1), which was primarily designed to investigate the pharmacokinetics of dispersible bosentan in pediatric patients, demonstrated that increasing the dosage of bosentan from 2 to 4 mg/kg twice daily was unlikely to result in increased exposure to bosentan. Exploratory measures of efficacy in FUTURE-1 demonstrated that target dosages of twice-daily dispersible bosentan 4 mg/kg (in patients weighing <30 kg) or 120 mg (in patients weighing > or =30 kg) for 12 weeks were beneficial in pediatric patients (aged > or =2 to <12 years) with WHO functional class II or III PAH. Film-coated bosentan 31.25, 62.5, or 125 mg (in pediatric patients weighing 10-20, >20-40, or >40 kg, respectively) twice daily for 12 weeks significantly (p < 0.05) improved the majority of hemodynamic measures evaluated as an exploratory measure in pediatric patients (aged 3-15 years) with WHO functional class II or III PAH in another noncomparative, multicenter, pharmacokinetic trial (BREATHE-3). However, there was no significant change in peak oxygen consumption or mean walk distance in those patients capable (i.e. children aged > or =8 years) of performing the 6-minute walk test. Bosentan was generally well tolerated in clinical trials of pediatric patients with PAH, with most adverse events being mild or moderate in severity and resolving with continued treatment.