Pharmacology Update

Ambrisentan Tablets (Letairis™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD; Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.

A second, orally active, endothelin receptor (ET) antagonist has been approved for the treatment of pulmonary arterial hypertension. Ambrisentan is more ETA selective than bosentan and is dosed once a day. The approval was granted orphan status by the FDA. Ambrisentan is marketed by Gilead Sciences, Inc as Letairis.


Ambrisentan is indicated for the treatment of pulmonary arterial hypertension (WHO Group 1) in patients with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening.1


The initial recommended dose is 5 mg once daily and may be increased to 10 mg daily if tolerated. The tablets may be taken without regard to meals. Ambrisentan is contraindicated in pregnancy and is not recommended in patients with moderate or severe hepatic dysfunction.1

Ambrisentan is available as 5 mg and 10 mg tablets.

Potential Advantages

Ambrisentan is about 4 times more selective for the ETA compared to ETB than bosentan (77:1 vs 20:1).2 It may be less hepatotoxic and is dosed more conveniently (once vs twice daily) compared to bosentan.

Potential Disadvantages

Ambrisentan may cause serious liver injury. Liver transaminases should be monitored monthly and the drug discontinued if levels are greater than 2 times ULN or any signs or symptoms of liver dysfunction. Other adverse events include peripheral edema, decreases in hemoglobin, nasal congestion, sinusitis, and flushing. Ambrisentan is metabolized by various CYP450 isoenzymes (3A4, 2C19), P-glycoprotein, uridine 5'-diphosphate glucuronosyltransferases, and organic anion transport protein (OATP). Caution should be exercised with co-administration of strong inhibitors or inducers of these enzymes or transport protein. These include, but are not limited to, protease inhibitors, rifampin, cyclosporine A, clarithromycin, intraconazole, and omeprazole.1


Pulmonary arterial hypertension is a rare but fatal disease characterized by progressive increase in pulmonary vascular resistance resulting in vascular remodeling, vasoconstriction and ultimately ventricular failure and premature death. The cause may be unknown (ie, idiopathic) or due to HIV infection or other diseases (eg, scleroderma). Endothelin-1 has been recognized as an important mediator in the pathogenesis and acceleration of this disease.2,3,4 Endothelin-1 binds to ETA and ETB. Binding to ETA results in vasoconstriction and mitogenic effect on smooth muscle, while binding to ETB induces vasodilatory and antiproliferation effects. The efficacy of ambrisentan was demonstrated in 2 international clinical trials of virtually identical design involving 393 patients (ARIES-1, ARIES-2).1 One study compared 5 mg and 10 mg to placebo, the other 2.5 mg and 5 mg to placebo. The primary endpoint was 6-minute walk distance. Secondary endpoints included clinical worsening, WHO functional class, dyspnea and SF-36 assessment. Statistically significant placebo-adjusted change in walk distance was 32 m, 31 m, and 59 m and 51 m for 2.5 mg, 5 mg and 10 mg respectively in the two studies. Clinical worsening showed about a 70% reduction (hazard ratio of 0.28 and 0.30). These results are similar in magnitude to that reported for bosentan.5 Adverse events include reduction in hemoglobin, peripheral edema, nasal congestion, sinusitis, and flushing. Serious adverse events include hepatotoxicity and lowering of sperm count. Ambrisentan is available only through the Letairis Education and Access Program (LEAP) (1-866-664-5327) and shipped only by participating specialty pharmacies.

Clinical Implications

It is estimated that there are 100,000 patients with pulmonary arterial hypertension in the US.7 Pharmacological treatment includes prostacyclin analog (eg, epoprostenol), ET inhibitors (bosentan and ambrisentan), and phosphodiesterase inhibitor (eg, sildenafil). Patients in function class or those who remain in class 3 after 4 months of treatment with an ET inhibitor may stand to benefit from epoprostenol.6 Ambrisentan may offer a safer alternative to bosentan in terms of hepatotoxicity. It may be tried in patients who have asymptomatic elevations of liver transaminases on other ET inhibitors if the levels have returned to normal.1 However, there is currently no evidence to indicate that the greater ETA selectivity over bosentan leads to any clear clinical advantage.


1. Letaris Product Information. Gilead Sciences, Inc. June 2007.

2. Langleben D. Clin Chest Med. 2007;28:117-125.

3. Galic N, et al. J Am Coll Cardiol. 2005;46:529-535.

4. Jacobs A, et al. Curr Med Res Opin. 2006;22:2567-2574.

5. Tracleer Product Information. Actelion Pharmaceuticals, Inc. 2005.

6. Provencher S, et al. Eur Heart J. 2006;27:589-595.

7., accessed 8/1/07.