When Bosentan Treatment Fails, Sitaxsentan May Help


SAN ANTONIO — Pulmonary arterial hypertension patients treated with bosentan whose condition deteriorates or who can't tolerate the drug may respond to a related medicine, sitaxsentan, a preliminary study suggests.

Like bosentan, sitaxsentan is an endothelin receptor antagonist, but it is much more selective for endothelin A. Bosentan blocks the activity of both endothelin A and endothelin B.

Endothelin is a potent endogenous peptide with vasoconstricting, mitogenic, and profibrotic effects. It appears to play a role in the pathology of pulmonary arterial hypertension associated with connective tissue disease.

“Although the relative importance of endothelin A versus endothelin B in pulmonary arterial hypertension remains unclear, selective antagonism of endothelin A may be advantageous in blocking the deleterious endothelin A vasoconstriction in the pulmonary vasculature while maintaining the vasodilator and clearance functions of the endothelin B receptor,” Adaani Frost, M.D., said in a poster session at the annual meeting of the American College of Rheumatology.

Although bosentan (Tracleer) has proven beneficial in this condition, many patients develop liver function abnormalities during treatment. Bosentan is metabolized by the liver, and the elevations in liver enzymes are thought to relate to an accumulation of bile salts. Sitaxsentan undergoes both hepatic and renal metabolism, and has no effect on bile salts or bilirubin, Dr. Frost explained.

In an effort to determine if the selective endothelin antagonist would provide an effective alternative to bosentan, 11 patients were enrolled in an open‐label study. Of these, three had developed liver function abnormalities, and eight experienced clinical deterioration during bosentan treatment. One patient who was New York Heart Association functional class IV at study entry died after 5 weeks of treatment with sitaxsentan and was not included in the analysis.

The remaining 10 have now been followed for 12 weeks. The mean improvement in 6‐minute walk time with sitaxsentan was 36.5 meters. Although the condition of four patients improved, five stabilized, and one's condition deteriorated, said Dr. Frost, professor of medicine, Baylor College of Medicine, Houston.

None of the patients who experienced liver function abnormalities on bosentan did so on sitaxsentan. One patient whose condition had deteriorated clinically experienced transient liver function abnormalities that resolved spontaneously and did not require cessation of the drug.

Ongoing studies should provide further information on using sitaxsentan in this population, Dr. Frost said.

The study was undertaken with a research grant from Encysive Pharmaceuticals, Bellaire, Tex.