Treprostinil
The prostacyclin analogue treprostinil has two key advantages over epoprostenol: it is stable at room temperature and its half-life is longer (three to four hours), permitting its administration as a subcutaneous infusion. In May 2002, the FDA approved the subcutaneous form of treprostinil (United Therapeutics’ Remodulin) for the treatment of pulmonary arterial hypertension patients in NYHA functional classes II, III and IV. An IV preparation of the agent (to be used in patients unable to tolerate the subcutaneous formulation) was approved by the FDA in November 2004, following studies showing bioequivalence with the subcutaneous formulation in patients with pulmonary arterial hypertension.
Treprostinil’s mechanism of action follows that outlined for prostacyclin analogues in general, and the agent’s vasodilatory, platelet inhibitory, and hemodynamic actions mirror those of epoprostenol.
A small pilot study investigated subcutaneous treprostinil versus placebo (2:1) in 26 pulmonary arterial hypertension patients who were NYHA functional classes III and IV. The follow-up period was eight weeks. An improvement in the 6MWD of 37 ± 17 m was seen in the treprostinil-treated group compared with 6 ± 28 m in the placebo group (results were not statistically significant). There was also a trend toward an improvement in hemodynamics (20% reduction in pulmonary vascular resistance over eight weeks) in the treprostinil group.
A 12-week, multicenter, randomized, placebo-controlled study investigated the actions of treprostinil (maximum dose 22.5ng/kg/min) in 470 pulmonary arterial hypertension patients (pulmonary arterial hypertension or patients with pulmonary arterial hypertension associated with connective tissue disease or congenital heart defects). The study’s primary end point was the 6MWD. Results showed an improvement in the treprostinil group and no improvement in the placebo group. The median difference in the 6MWD between the two groups was 16 m (p = 0.006), and improvements were shown to be dose-dependent. Those patients receiving doses greater than 13.8ng/kg/min experienced an improvement of 36 m. The treprostinil group also experienced improvements in indices of dyspnea, signs and symptoms of pulmonary hypertension, and hemodynamics. The effect of treprostinil on the 6MWD was rather modest compared with trials investigating epoprostenol, but researchers have suggested that entry criteria for this study were much broader than those for the epoprostenol studies. Patients who entered the study as NYHA functional class IV showed an improvement in the 6MWD of 54 m, which is comparable to that of other clinical investigations. Long-term efficacy (more than 12 weeks) was not included in this study; however, open-label studies suggest that improvements in exercise capacity are maintained.
In October 2003, the results of a small study of treprostinil were presented at the 54th Annual Meeting of the American Association for the Study of Liver Diseases in Boston. The study, which involved 37 patients, demonstrated that treprostinil is safe in patients with pulmonary arterial hypertension associated with portal hypertension/liver disease. The drug also maintained or improved the hemody-namics in the majority of the patients in the study group. The safety profile followed that of the studies outlined in the following paragraph.
Clinical studies evaluating the IV preparation of treprostinil are limited. One multicenter, open-label, acute trial compared the effects of IV epoprostenol with IV treprostinil. Fourteen pulmonary arterial hypertension patients were enrolled in the study. Following right-heart catheterization, epoprostenol was administered by IV infusion at 2ng/kg/min and increased at 15- to 30-minute intervals by 2ng/kg/min intervals to a maximum-tolerated dose; hemodynamic measurements were taken along the way. Epoprostenol was then washed out, and after a 90-minute rest period, 5 ng/kg/min of treprostinil was administered for 30 minutes and increased every 30 minutes to 10, 20, 30, 40, and 60 ng/kg/min. Dose ranging was carried out until dose side effects warranted a dose reduction or discontinuation of therapy (nontolerated dose). A 90-minute maintenance dose was continued at 10-20 ng/kg/min below the nontolerated dose; it was followed by a 120-minute washout period. Results showed the maximum-tolerated dose of IV epoprostenol was 6.4 ± 0.8 ng/kg/min and that of treprostinil was 24 ± 4.0 ng/kg/min. Adverse events were similar in both groups and included jaw pain, headache, nausea, chest pain, backache, and restlessness. Similar reductions in pulmonary artery pressure also occurred. There was a 22% reduction in pulmonary vascular resistance for epoprostenol compared with a 20% reduction in pulmonary vascular resistance for treprostinil (differences were not statistically significant). One patient experienced a serious adverse event during the maintenance infusion due to a documented foramen ovale (atrial septal defect); the patient recovered after the infusion was terminated.
A randomized crossover study design compared the bioequivalence and comparative pharmacokinetics of subcutaneous and IV treprostinil in 51 healthy volunteers. Results showed that IV and subcutaneous treprostinil were bioequivalent at a steady state. Treprostinil’s elimination half-life was 4.4 and 4.6 hours following IV and subcutaneous administration, respectively.
Common side effects associated with treprostinil therapy in clinical trials include headache, diarrhea, nausea, rash, and jaw pain. More importantly, infusion-site pain was commonly reported in studies of the subcutaneous preparation; 85% of patients in the large multicenter study of subcutaneous treprostinil complained of pain around the site of infusion, and 83% reported erythema (redness of the skin) or induration of the infusion site. United Therapeutics is working closely with health care professionals in the pulmonary arterial hypertension field to address the issue of infusion-site pain. The company also provides a free telephone advisory service for treprostinil patients, known as the Remodulin Therapy Assistance Program. This problem of infusion site pain was the driving force behind the company’s investigation of an IV formulation. A smaller pump size makes the IV formulation of treprostinil potentially more attractive than IV epoprostenol to physicians.
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