Pharmacokinetic evaluation of treprostinil (oral) for the treatment of pulmonary arterial hypertension

Introduction: This review summarizes current information on the first oral prostanoid approved for treatment of pulmonary arterial hypertension, treprostinil diolamine, which, similar to other prostacyclin analogs, vasodilates, impacts remodeling (antiproliferative), reduces endothelial cell dysfunction, inhibits platelet aggregation (antithrombotic) and increases right heart inotropy. Areas covered: From a pharmacological point of view, it appears that with sustained blood concentrations for 8 - 10 h after a single dose, twice or thrice daily dosing is possible. This review discusses three randomized trials of oral treprostinil that have been completed (FREEDOM-M, FREEDOM-C, FREEDOM-C2). FREEDOM-C and -C2 evaluated oral treprostinil in patients on stable background therapy; FREEDOM-M evaluated oral treprostinil as monotherapy. In FREEDOM-M, the primary end point (6-minute walk distance; 6MWD) was attained, but was not reached in either FREEDOM-C trial. As such, the FDA did not grant approval. Thus, another clinical trial (FREEDOM-EV) is underway: oral treprostinil in patients on background therapy evaluating co-primary end points: i) change in 6MWD; and ii) occurrence of predetermined events. In the interim, oral treprostinil was approved in December 2013. Expert opinion: The use and future of oral treprostinil is not clear. This will depend on the ability to titrate the drug to high levels with acceptable tolerance, on the results of FREEDOM-EV trial and on the impact of selexipag and other oral prostanoids being developed.