Ambrisentan for the management of pulmonary arterial hypertension.
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 <or= 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 by patients with PAH, and its efficacy relative to other agents used to manage PAH.
Massachusetts College of Pharmacy and Health Sciences and Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. judy.cheng@mcphs.edu
Judy W M
JW
Cheng
D000818:Animals; D004347:Drug Interactions; D065130:Endothelin A Receptor Antagonists; D005260:Female; D048550:Hepatic Insufficiency / Q000150:complications / Q000503:physiopathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000188:drug therapy*; D007774:Lactation / Q000378:metabolism; D008297:Male; D010666:Phenylpropionates / Q000008:administration & dosage / Q000009:adverse effects / Q000191:economics / Q000627:therapeutic use*; D011247:Pregnancy; D011724:Pyridazines / Q000008:administration & dosage / Q000009:adverse effects / Q000191:economics / Q000627:therapeutic use*; D051437:Renal Insufficiency / Q000150:complications / Q000503:physiopathology
D065130:Endothelin A Receptor Antagonists; D010666:Phenylpropionates; D011724:Pyridazines; C467894:ambrisentan