PURPOSE: Treprostinil diethanolamine (UT-15C) is a prostacyclin analog currently being evaluated as a sustained release (SR) osmotic tablet for the treatment of pulmonary arterial hypertension (PAH). Previous studies have demonstrated an improved pharmacokinetic profile with UT-15C administration following a 500 calorie meal as compared to fasting. Furthermore, anecdotal reports from investigators participating in clinical trials with UT-15C have suggested that some PAH patients may experience decreased tolerability with decreased caloric intake. To better understand the effect of food on UT-15C pharmacokinetics, we evaluated the effect of four different meal compositions on UT-15C exposure.
METHODS: This was a single-center, randomized, open-label, cross-over study in which healthy volunteers were given UT-15C SR 1 mg immediately following one of four pre-specified meals consisting of a 500 calorie well balanced meal (Meal A), a 250 calorie well balanced meal (Meal B), a 250 calorie high fat meal (Meal C), and a 250 calorie well balanced liquid meal supplement (Meal D; Ensure(r)). Each dose of UT-15C was separated by a 7-day washout period. Eighteen blood samples were obtained over 36 hours with plasma concentrations of treprostinil quantified by liquid chromatography/mass spectrometry. Safety was assessed via adverse event reporting, clinical laboratories, physical exams, and ECGs.
RESULTS: Thirty-two healthy male and female volunteers were enrolled. Administration of UT-15C immediately following Meal A resulted in 12%, 3% and 7% greater exposure than that observed following administration after Meals B, C and D, respectively. Half-life was approximately 3-5 hours. Headache was the most common prostacyclin related adverse event (3 reports). There were no clinically significant treatment emergent changes in clinical laboratories, ECGs or vital signs.
CONCLUSION: Decreased caloric and fat intake resulted in consistent but clinically insignificant decreases in exposure to UT-15C in healthy volunteers.
CLINICAL IMPLICATIONS: Although the pharmacokinetic impact of varying meal compositions on UT-15C exposure was not found to be clinically significant in healthy volunteers, PAH patients may experience improved tolerability with increased fat and/or caloric intake.
DISCLOSURE: Allison Lim, Employee Allison Lim, Susan Walker, Jennifer Kates and Kevin Laliberte are employees of United Therapeutics Corporation.; Product/procedure/technique that is considered research and is NOT yet approved for any purpose. Treprostinil diethanolamine