Clinical use of extended-release oral treprostinil in the treatment of pulmonary arterial hypertension

Abstract

The development of parenteral prostacyclin therapy marked a dramatic breakthrough in the treatment of pulmonary arterial hypertension (PAH). Intravenous (IV) epoprostenol was the first PAH specific therapy and to date, remains the only treatment to demonstrate a mortality benefit. Because of the inherent complexities and risks of treating patients with continuous infusion IV therapy, there is great interest in the development of an oral prostacyclin analog that could mimic the benefits of IV therapy. Herein, we highlight the development of oral prostacyclin therapy, focusing on oral treprostinil, the only US Food and Drug Administration approved oral prostacyclin. Recent Phase III clinical trials have shown the drug to improve exercise tolerance in treatment-naïve PAH patients, but not patients on background oral therapy. Oral treprostinil appears to be most efficacious at higher doses, but its side effect profile and complexities with dosing complicate its use. While oral treprostinil's current therapeutic role in PAH remains unclear, ongoing studies of this class of medication should help clarify their role in the treatment of PAH.

Keywords: oral treprostinil; pulmonary arterial hypertension; selexipag.

Figure 1

Mean concentration–time profiles of treprostinil diolamine (UT-15C): 2 and 6 mg. Notes: Subjects had blood samples drawn before the morning dose (t=0) and then 0.5, 1, 2, 4, 6, 8, and 12 hours after a meal and the dose of treprostinil diolamine. The dose on the prior evening was taken between 11 and 13 hours before time t=0. Vertical bars show standard deviation; the shaded gray area corresponds approximately to plasma levels when patients are using parenteral treprostinil doses between 10 and 30 ng/kg/min. Reproduced with permission from White RJ, Torres F, Allen R, et al. Pharmacokinetics of oral treprostinil sustained release tablets during chronic administration to patients with pulmonary arterial hypertension. J Cardiovasc Pharmacol. 2013;61(6):474–481. Promotional and commercial use of the material in print, digital or mobile device format is prohibited without the permission from the publisher Wolters Kluwer Health. Please contact healthpermissions@wolterskluwer.com for further information

Figure 2

Mean steady-state daily plasma treprostinil concentration after 0.5 mg TID regimen. Notes: The downward arrows represent the times at which doses were given. Patients received 8 days of oral treprostinil, data was obtained on day 7. N=19. Reproduced with permission from Jones A, Wang-Smith L, Pham T, Laliberte K. Pharmacokinetics of 3 times a day dosing of oral treprostinil in healthy volunteers. J Cardiovasc Pharmacol. 2014;63(3):227–232. Promotional and commercial use of the material in print, digital or mobile device format is prohibited without the permission from the publisher Wolters Kluwer Health. Please contact healthpermissions@wolterskluwer.com for further information Abbreviation: TID, three times a day.