Ambrisentan is an endothelin receptor antagonist used in the therapy of pulmonary arterial hypertension (PAH). Ambrisentan has been associated with a low rate of serum enzyme elevations during therapy, but has yet to be implicated in cases of clinically apparent acute liver injury.
Ambrisentan (am" bri sen' tan) is a selective inhibitor of the endothelin receptor type A (ETA) and has little activity against ETB in the doses used in humans. Inhibition of the ETA receptor disrupts the intracellular pathways that lead to vasoconstriction, thus causing vasodilation. Because this receptor is found in highest concentration in the lungs, ambrisentan primarily causes vasodilation in the pulmonary vasculature and decreases pulmonary vascular pressure. In prospective, randomized controlled trials, ambrisentan was effective in alleviating symptoms, improving exercise tolerance and prolonging the time to clinical worsening in patients with idiopathic PAH. Ambrisentan was the second endothelin receptor antagonist to be approved in the United States (2007) and it remains in active use. The current indications are for symptomatic pulmonary arterial hypertension, classified as WHO group 1 (idiopathic). Use of ambrisentan in other forms of PAH (due to heart failure, thromboembolic disease, or pulmonary disease) should be considered experimental as its efficacy in these forms of PAH has not been adequately shown. Because of the potential for teratogenicity, ambrisentan is available only as a part of a monitoring program in which documentation of adequate methods for birth control are required. Ambrisentan is available in tablets of 5 and 10 mg under the brand name Letairis and the recommended dose is 5 to 10 mg once daily. Common side effects include headaches, dizziness, edema, flushing, rhinitis and dyspepsia.
Ambrisentan is associated with a low rate of serum aminotransferase elevations (0% to 3%) that in clinical trials was similar to the rate in placebo recipients. These elevations are usually mild (rarely above 3 times ULN), transient and not associated with symptoms. For these reasons, monthly monitoring of serum aminotransferase levels is no longer routinely recommended during ambrisentan therapy.
There have also been no published reports of clinically apparent liver injury with jaundice associated with ambrisentan, but it has had limited general use. Other endothelin receptor antagonists (bosentan, sitaxsentan) have been linked to cases of acute liver injury, some of which have been severe. The onset of illness was usually within 1 to 6 months of starting bosentan and the enzyme pattern was typically hepatocellular or mixed. Immunoallergic features were usually not present and autoantibodies absent or present in low titer. Sitaxsentan was linked to several cases of fatal acute liver failure, for which reason it was not approved in the United States and was later withdrawn from use elsewhere. Ambrisentan has not been linked to similar cases and its chemical structure is sufficiently different to suggest lack of cross sensitivity to this complication.
Likelihood score: E (unlikely cause of clinically apparent liver injury).
Mechanism of Injury
The mechanism by which ambrisentan might cause liver injury is not known. Ambrisentan is metabolized by the cytochrome P450 system (CYP 2C9 and 3A4), which may lead to production of a toxic intermediate and can also cause drug-drug interactions, particularly with cyclosporine A. One reason why ambrisentan may have less potential for causing liver injury than does bosentan is that its total daily dosage is much less, 5 to 10 mg daily rather than 62.5 to 125 mg.
Outcome and Management
The serum enzyme elevations associated with ambrisentan use have been mild-to-moderate and self-limited in course, often resolving despite drug continuation. Most patients who have had serum enzyme elevations while taking bosentan have tolerated switching to ambrisentan, but in at least one case report there was recurrence of liver injury, indicating that patients switched from one endothelin-1 receptor antagonist to another should be monitored at least for the first several months after switching.
REPRESENTATIVE TRADE NAMES
Ambrisentan – Letairis®
Pulmonary Arterial Hypertension Agents
Product labeling at DailyMed, National Library of Medicine, NIH
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