Ambrisentan for the treatment of pulmonary arterial hypertension

Abstract

Ambrisentan is an endothelin receptor antagonist (ERA) that was recently approved for treatment of pulmonary arterial hypertension (PAH). Endothelin (ET) is a potent vasoconstrictor with mitogenic, hypertrophic and pro-inflammatory properties that is upregulated in pulmonary hypertensive diseases. The biologic effects of ET are mediated by 2 cell surface receptors termed ET(A) and ET(B). ET(A) mediates the vasoconstrictor effect of ET on vascular smooth muscle, whereas ET(B) is expressed primarily on vascular endothelial cells where it induces nitric oxide synthesis and acts to clear ET from the circulation. Ambrisentan is the first ET(A) selective ERA approved for use in the US. Recently published clinical trials in patients with PAH demonstrate improvement in functional capacity and pulmonary hemodynamics similar to other ET(A) selective and non-selective ERAs. Its once daily dosing and lower incidence of serum aminotransferase elevation offer potential advantages over other ERAs, but further experience with this agent is needed to fully understand its long-term efficacy and safety. This review discusses the endothelin family of proteins and receptors and their role in the pathophysiology of pulmonary hypertensive diseases. It also examines the development process, safety profile and clinical trials that have resulted in ambrisentan being approved for treatment of PAH.

Keywords: ambrisentan; endothelin; endothelin receptor antagonist; pulmonary hypertension.

Figure 1

Molecular structure of ambrisentan.

Figure 2

Changes from baseline in the 6-minute walking distance at week 12 in the placebo and ambrisentan groups from the ARIES-1 and ARIES-2 studies. For ARIES-1, p = 0.008 and p < 0.001 for the 5-mg and 10-mg ambrisentan groups vs placebo, respectively. In ARIES-2, p = 0.022 and p < 0.001 for the 2.5-mg and 5-mg ambrisentan groups vs placebo, respectively. Values shown are mean ± SE. Reproduced with permission from Galie N, Olschewski H, Oudiz RJ, et al 2008. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation, 117:3010–9. Copyright © 2008. Lippincott Williams & Wilkins.

Figure 3

Kaplan-Meier estimates of the proportion of patients with clinical worsening in the ARIES-1 and ARIES-2 studies. See text for definition of clinical worsening. In ARIES-1, no significant differences were seen between the ambrisentan 5-mg and 10-mg groups vs placebo or the 5-mg and 10-mg groups combined vs placebo. In ARIES-2, p = 0.005, p = 0.008, and p < 0.001 for the ambrisentan 2.5-mg, 5-mg, and 2.5 plus 5-mg dose groups combined, respectively. Reproduced with permission from Galie N, Olschewski H, Oudiz RJ, et al 2008. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation, 117:3010–9. Copyright © 2008. Lippincott Williams & Wilkins.