Ambrisentan for the management of pulmonary arterial hypertension

• Published in: Clinical therapeutics 2008-05, Vol.30 (5), p.825-833
• Main Author: Cheng, Judy W.M., BS, PharmD, MPH, FCCP, BCPS
• Format: Article
• Language: English
• Subjects: ambrisentan; Animals; Biological and medical sciences; Drug Interactions; Endothelin A Receptor Antagonists; endothelin-receptor antagonist; Female; Hepatic Insufficiency - complications; Hepatic Insufficiency - physiopathology; Humans; Hypertension, Pulmonary - complications; Hypertension, Pulmonary - drug therapy; Internal Medicine; Lactation - metabolism; Male; Medical Education; Medical sciences; Pharmacology. Drug treatments; Phenylpropionates - administration & dosage; Phenylpropionates - adverse effects; Phenylpropionates - economics; Phenylpropionates - therapeutic use; Pneumology; Pregnancy; pulmonary arterial hypertension; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Pyridazines - administration & dosage; Pyridazines - adverse effects; Pyridazines - economics; Pyridazines - therapeutic use; Renal Insufficiency - complications; Renal Insufficiency - physiopathology
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2008.05.005

Abstract Background: Approved by the US Food and Drug Administration in 2007, ambrisentan is the second oral endothelin A-receptor antagonist available for the management of pulmonary arterial hypertension (PAH) in patients with World Health Organization class II or III symptoms. Objective: This article examines the clinical pharmacology of ambrisentan, its efficacy and adverse effects, and future directions for research. Methods: Pertinent articles and abstracts were identified through searches of MEDLINE and Current Contents from 1966 to January 15, 2008, using the term ambrisentan . The reference lists of identified articles were searched for additional publications. Abstracts presented at professional meetings from 2005 through 2007 were also reviewed. Results: The literature review identified 3 studies of ambrisentan in PAH: 1 dose-ranging study; 2 randomized, double-blind, placebo-controlled studies; and 1 drug-conversion study. In the dose-ranging study, ambrisentan at doses of 1 to 10 mg was associated with significant improvements from baseline in the 6-minute walk distance at 12 weeks that ranged from 33.9 m with ambrisentan 1 mg ( P = 0.003) to 38.1 m with ambrisentan 5 mg ( P = 0.001). In the placebo-controlled studies, ambrisentan at doses of 2.5 to 10 mg/d was associated with significant improvements versus placebo in the 6-minute walk distance at 12 weeks that ranged from 22 m with ambrisentan 2.5 mg ( P = 0.022) to 59 m with ambrisentan 5 mg ( P ≤ 0.001). Improvements were sustained for up to 1 year. Patients who had elevations in serum aminotransferases during previous therapy with bosentan or sitaxsentan therapy were able to make a successful transition to ambrisentan without further abnormalities in liver function. Ambrisentan was generally well tolerated. The most common adverse effects associated with ambrisentan in clinical trials were peripheral edema (17%), nasal congestion (6%), palpitation (5%), constipation (4%), flushing (4%), abdominal pain (3%), nasopharyngitis (3%), and sinusitis (3%). In the placebo-controlled studies, the incidence of liver aminotransferase and bilirubin abnormalities at 12 weeks was lower with ambrisentan than with placebo (0.8% vs 2.3%, respectively). Conclusions: The available evidence suggests that ambrisentan is effective and well tolerated in the management of PAH. Areas for future research include the long-term safety of ambrisentan, its potential for drug interactions with other agents commonly used