Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive, fatal disease with no cure. Parenteral and inhaled prostacyclin analogue therapies are effective for the treatment of PAH, but complicated administration requirements can limit the use of these therapies in patients with less severe disease. This study was designed to evaluate the safety and efficacy of the oral prostacyclin analogue treprostinil diolamine as initial treatment for de novo PAH. METHODS AND RESULTS: Three hundred forty-nine patients (intent-to-treat population) not receiving endothelin receptor antagonist or phosphodiesterase type-5 inhibitor background therapy were randomized (treprostinil, n=233; placebo, n=116). The primary analysis population (modified intent-to-treat) included 228 patients (treprostinil, n=151; placebo, n=77) with access to 0.25-mg treprostinil tablets at randomization. The primary end point was change from baseline in 6-minute walk distance at week 12. Secondary end points included Borg dyspnea index, clinical worsening, and symptoms of PAH. The week 12 treatment effect for 6-minute walk distance (modified intent-to-treat population) was 23.0 m (P=0.0125). For the intent-to-treat population, 6-minute walk distance improvements were observed at peak (26.0 m; P=0.0001) and trough (17.0 m; P=0.0025) plasma study drug concentrations. Other than an improvement in the combined 6-minute walk distance/Borg dyspnea score, there were no significant changes in secondary end points. Oral treprostinil therapy was generally well tolerated; the most common adverse events (intent-to-treat) were headache (69%), nausea (39%), diarrhea (37%), and pain in jaw (25%). CONCLUSIONS: Oral treprostinil improves exercise capacity in PAH patients not receiving other treatment. Oral treprostinil could provide a convenient, first-line prostacyclin treatment option for PAH patients not requiring more intensive therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00325403.

Pharmacokinetics of oral treprostinil sustained release tablets during chronic administration to patients with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive vascular disease that ultimately leads to right ventricular failure and death. Treprostinil diolamine is an oral prostacyclin analogue; sustained release tablets of oral treprostinil are currently being evaluated for efficacy and safety as a potential therapy in patients with PAH. Previous attempts at developing an oral prostanoid have been limited by rapid absorption and short plasma half-life; thus, the aim of this study was to characterize the pharmacokinetic profile of treprostinil diolamine in PAH patients after chronic dosing. The study enrolled 74 PAH patients who had been taking treprostinil diolamine for a minimum of 4 weeks (range: 0.5-16 mg). We collected plasma samples over 12 hours and estimated pharmacokinetic parameters using noncompartmental methods. Seventy patients had complete data. After chronic twice-daily oral dosing of treprostinil diolamine, mean area under the curve (AUC0-12) of treprostinil increased from 5244 to 20,4086 pg·hr-·mL- and mean maximum observed plasma concentration (Cmax) increased from 1383 to 33588 pg/mL. The apparent clearance (CL/F) was similar across all doses, indicating a linear dose-exposure relationship after twice-daily dosing. We conclude that twice-daily oral treprostinil provides sustained and proportional treprostinil concentrations over a wide range of doses during chronic administration to PAH patients.