Ambrisentan (manufactured under the trade names Letairis in the U.S., Volibris in the European Union, and Pulmonext in India) is an FDA-approved oral formulation for treating patients with pulmonary hypertension (PH).

Chemically, it is denoted as (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid, and is an endothelin receptor antagonist (ETA), selective for  the endothelin type-A (ETA) receptor. It is recommended for use in patients with WHO classes II and III symptoms of pulmonary arterial hypertension, to improve exercise ability and delay clinical worsening.

How Letairis (Ambrisentan) Works

Endothelin-1 (ET-1) is a protein molecule responsible for both autocrine (same cell) and paracrine (cell to cell) signaling, and ETA and ETB are receptors responsible for binding of ET-1 to mediate their effects on vascular smooth muscle. ETA is responsible for vasoconstriction and cell proliferation, and ETB mediates vasodilation, anti-proliferation and ET-1 clearance.

In patients with PAH, there is a tenfold increase in the amount of plasma ET-1 concentration, along with a ninefold increase in pulmonary arterial endothelium and an increase in vasoconstriction indicates a rise in ETA levels as well. In these cases, ambrisentan acts as the antagonist for these ET-1 peptides, with a strong affinity for ETA receptors. This helps in regulating the balance between ETA and ETB, ensuring vasodilation.

Letairis (Ambrisentan) Clinical Trials

Gilead, the manufacturer of Letairis in the United States, had submitted a New Drug Application (NDA) to the FDA in December 2006, followed by an FDA  priority review status. Successful results from two main clinical trials, ARIES-1 and ARIES-2, both of which were 12-week, randomized, double-blind, placebo-controlled, multicenter studies, provided convincing evidence for the FDA to approve the drug for use in PH patients in June 2007.

The ARIES-1 and ARIES-2 trials demonstrated improvements in the study population based on different dosage strengths (2.5, 5, and 10 mg daily) and measured their efficacy in terms of the distance traversed from baseline in the 6-minute walk distance (6MWD) test, in comparison to a placebo. Moreover, in both cases it was seen that clinical worsening was lower by a significant amount as compared to those receiving placebos. Apart from these two trials, another study published in the August 2015 issue of the New England Journal of Medicine (NEJM) showed that ambrisentan when used in combination with tadalafil (another FDA-approved drug for treating PAH) was more effective in improving patient health and slowing clinical worsening of the disease.

Dosing for Letairis (Ambrisentan)

Dosage for ambrisentan ranges from 5 mg to 10 mg once daily, taken orally. It is generally not advisable for female patients to take the drug during pregnancy. Expert opinion is always recommended before prescribing the drug to expectant mothers or those planning to conceive a child. The most common side effects associated with the drug include peripheral edema, nasal congestion, constipation, flushing, palpitation, upper respiratory tract infections, loss of appetite, and dizziness. Some of the more severe consequences include low RBC levels (anemia), low sperm counts, swelling of the entire body and birth defects.

Note: Pulmonary Hypertension News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.

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