Iloprost
Iloprost is a stable analogue of epoprostenol (prostacyclin; PGI2). In contrast to epoprostenol, which must be dissolved, continuously cooled, and protected from light to ensure maximal activity, iloprost is stable at room temperature and in normal light. It has a half-life of 20-25 minutes. Iloprost can be administered intravenously (Schering AG’s Ilomedin/Ilomedine, marketed only in Germany) as an alternative to epoprostenol, but more interestingly, it is available as an inhaled preparation (Schering AG’s Ventavis, available in Europe) that is administered six to nine times daily. Each inhalation requires 10-15 minutes; some devices can reduce the inhalation time to 4 minutes. The use of an inhaled prostacyclin analogue is particularly attractive to patients who often experience variations in systemic blood pressure — for example, those with portopulmonary hypertension.
In December 2004, Cotherix, the company developing inhaled iloprost for the U.S. market, received FDA approval for the agent. Reports suggest the U.S. label for inhaled iloprost will permit the agent to be used to treat a much wider pulmonary hypertension population compared with that specified on the European label. Administration of the agent will also be less cumbersome in the United States because Cotherix has an agreement with Profile Drug Delivery that will enable iloprost to be delivered via a handheld nebulizer system.
Iloprost’s mechanism of action follows that outlined for the prostacyclin analogues in general. Treatment causes direct vasodilation of pulmonary and systemic vascular beds via activation of prostanoid receptors. Like all prostacyclin analogues, iloprost inhibits platelet activation.
A large-scale, randomized, placebo-controlled trial performed in Europe investigated the effects of inhaled iloprost (average daily dose of 30 micrograms over six to nine inhalations). The study involved 203 patients in NYHA functional classes III and IV with pulmonary arterial hypertension or pulmonary arterial hypertension associated with appetite suppressant use, collagen vascular disease, or inoperable thromboembolic disease. The initial follow-up period was 12 weeks. The primary end point was an improvement in NYHA functional class, at least a 10% improvement in the 6MWD, and no deterioration or death. Results showed that 16.8% of patients in the inhaled iloprost group compared with 4.9% in the placebo arm (p = 0.007) met the combined clinical end point. Increases in the 6MWD were 36.4 m in the iloprost group (p = 0.004); in the subgroup of patients with pulmonary arterial hypertension, the increases were 58.8 m. Hemodynamics deteriorated in the placebo group but not in the iloprost group. The number of patients remaining on medication, a proxy for event-free survival, was significantly higher in the iloprost group.
An open-label, multicenter study investigated the long-term treatment benefits of inhaled iloprost in 63 pulmonary arterial hypertension patients (40 with pulmonary arterial hypertension and 23 with associated pulmonary arterial hypertension) over a two-year period, which included a three-month randomized phase. The mean daily dose administered was 100 micrograms (over an average of six inhalations). During the course of the investigation, 5 patients switched from inhaled iloprost to alternative therapy (primarily IV iloprost) but remained in the study; 13 patients discontinued the therapy altogether. After the two-year follow-up, 37 patients were receiving therapy with inhaled iloprost. Eight patients died during the study period — three with pulmonary arterial hypertension and five with associated pulmonary arterial hypertension (two patients before receiving iloprost treatment). The survival rate measured by Kaplan-Meier analysis was 0.850 for all pulmonary arterial hypertension patients and 0.914 for those with pulmonary arterial hypertension for the two-year period. The predicted survival rate for pulmonary arterial hypertension patients (taken from previous studies) was 0.631, which corresponds to about 14.8 deaths. Given that only three pulmonary arterial hypertension patients died, treatment with iloprost appears to result in substantial improvement.
Clinical studies have shown inhaled iloprost to be well tolerated. Side effects more frequently encountered in the iloprost group compared with placebo include headache, cough, and flushing. A more serious side effect associated with iloprost is syncope; indeed, there were signs of clinical deterioration due to this adverse effect.
A small comparative study compared IV epoprostenol with IV iloprost in eight patients with severe pulmonary hypertension (five with pulmonary arterial hypertension and three with
thromboembolic pulmonary hypertension). A continuous infusion of either drug was given during the first phase (three to six weeks), and patients were then crossed over to receive the alternative agent for an equivalent period. Both epoprostenol and iloprost treatment significantly improved exercise tolerance. The results suggest IV iloprost is a suitable alternative to epoprostenol therapy in this extremely vulnerable patient group.
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