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Actelion's Tracleer approved for PAH
It's a condition that affects a limited number of people, so getting good epidemiologic data on the disease is difficult. What "it" refers to is pulmonary arterial hypertension (PAH). Simon Buckingham, president of Actelion USA, estimates that "there are approximately 5,000 patients in the United States that suffer from primary PAH and 50,000 or so that have PAH secondary to another disorder."
PAH is a chronic, life-threatening condition that compromises both heart and lung function due to vasoconstriction within the pulmonary vascular system. Over time, heart damage occurs, followed by scarring and fibrosis within the pulmonary arterial system. Although the precise cause of PAH is unknown, research has demonstrated that in affected patients, serum concentrations of endothelin-1 (ET-1) are significantly elevated. "Under pathologic conditions, endothelin is made massively in the lungs," said Buckingham.
ET-1 is the body's most potent vasoconstrictor hormone. When it binds to its receptors in the walls of the vasculature, vasoconstriction results. As resistance to blood flow increases, the blood vessel walls become fibrous and scarred. This is accompanied by cardiac muscle deterioration, which develops under the continuous strain.
Although PAH may occur in isolation, it more commonly results as a secondary complication of other conditions such as scleroderma, lupus, HIV/AIDS, congenital heart diseases, or fen-phen appetite-suppressant therapy. Early signs of the disease include shortness of breath, fatigue, and exercise intolerance; as such, the disease is often misdiagnosed until patients deteriorate. When untreated, two-year survival rates from symptom onset are only 40%-55%.
Until now, treatment for advanced disease involved either the vasodilating prostacylin, epoprostenol (Flolan, GlaxoSmithKline), or a lung transplant. According to Andy Doedyns, R.Ph., director of pharmacy at Gentiva Health Services, a provider of specialty pharmaceutical services, the decision to begin epoprostenol therapy requires a considerable patient commitment because, "Flolan must be delivered 24 hours a day via a central indwelling catheter." The drug is delivered directly into the heart, leading to an increased risk of thrombosis and infection. Also, patients must reconstitute the drug and keep it refrigerated and protected from light. Brief interruptions in delivery result in rapid symptomatic deterioration. As a result, patients want other therapeutic options.
Now, for the first time, with the approval of bosentan (Tracleer, Actelion) there is an oral pill available to treat PAH. Richard Channick, M.D., associate professor of medicine and pulmonary and critical care at the University of California San Diego Medical Center, said, "The biggest advantage of bosentan is that it's an oral drug."
"Instead of just acting as a vasodilator, Bosentan acts as a disease modifier to stop scarring before it occurs," said Doedyns.
Bosentan is a new molecular entity that acts as an ET-1 receptor antagonist. Blockade of ET-1 receptors constrains ET-1-mediated vasoconstrictive activity. In clinical trials, bosentan significantly increased exercise capacity and cardiac index and decreased pulmonary arterial pressure, mean right arterial pressure, and pulmonary vascular resistance. Over all, bosentan slowed the rate of clinical worsening in PAH patients.
Patients should take either 62.5-mg or 125-mg bosentan tablets twice daily. The product's label carries two black box warnings that highlight its potential to cause serious liver injury as well as possible teratogenic effects. Due to concern over liver damage, serum aminotransferase levels must be monitored prior to initiation of therapy and monthly thereafter. So far, elevated liver enzymes have resolved either with treatment interruption or cessation. In women of childbearing age, pregnancy must be excluded before initiating treatment, and monthly pregnancy tests must be conducted. Because bosentan induces liver metabolism, hormonal contraceptives should not be relied upon as the only means of contraception; other barrier methods must also be used.
Bosentan will be available only through a limited-distribution network from specialty pharmaceutical firms such as Gentiva. Of the limited drug distribution, Buckingham said it "ensures good safety and customer service. It also allows for convenient handling of reimbursement issues."
While clearly a significant advance, "bosentan is not a cure, but a tool, and patients are very excited about it," Doedyns concluded.
Kelly Karpa. New drug considered better way to treat pulmonary hypertension. Drug Topics 2002;1:20.