Extended-release oral treprostinil in the management of pulmonary arterial hypertension: clinical evidence and experience

Abstract

Treprostinil diolamine is the first oral prostacyclin approved for the treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity. Clinical studies have demonstrated modest benefit as monotherapy, whereas no difference in exercise capacity was observed with combination therapy. However, these trials were limited by subtherapeutic dosing owing to intolerable adverse effects. Prostacyclin-related adverse effects, such as nausea, diarrhea, headache, flushing, and jaw pain, are prevalent. More recent pharmacokinetic and clinical studies illustrate the dose–response relationship and the importance of achieving clinically effective doses. Therefore, efforts to improve tolerability are paramount. Oral treprostinil is recommended to be administered three times daily in order to facilitate more rapid titration, higher doses achieved, and improved tolerability. Oral treprostinil has also been studied in carefully selected, stable patients that transitioned from parenteral or inhaled therapy with close monitoring for late deterioration. Ongoing clinical trials will determine the long-term effects of higher doses of oral treprostinil on clinical outcomes. This review describes the clinical evidence and practical experience with the use of oral treprostinil for PAH.

Management of Pulmonary Arterial Hypertension in the Pediatric Patient

“…Treprostinil, available in intravenous (Remodulin), subcutaneous (Remodulin), oral (orenitram) and inhaled (Tyvaso) formulations, has a more favorable side effect profile than the aforementioned prostanoid agents. Though no formulation is approved for use in children, multiple studies have demonstrated safety with IV, subcutaneous, and inhaled preparations (55)(56)(57). Subcutaneous treprostinil is the most commonly used systemic preparation in children, as it reduces the infectious risk of indwelling intravenous lines and the potential risk of paradoxical air or thrombo-embolism in patients with unrepaired shunt lesions.…”

Comparative effectiveness of oral prostacyclin pathway drugs on hospitalization in patients with pulmonary hypertension in the United States: a retrospective database analysis

“… 31 Compared with prostanoids, selexipag has greater selectivity for the IP receptor, leading to reduced gastrointestinal intolerance, which has been a dose-limiting side effect with oral treprostinil. 32 , 33 A recent Delphi panel on the use of oral treprostinil suggested aggressive antidiarrheal medication to manage these adverse effects but failed to reach consensus on optimal dosing strategies. 34 In FREEDOM-EV, oral treprostinil was dosed three times a day (TID); 21 although this could help reduce the intensity of adverse effects to allow increasing the dose to a therapeutic level, 34 TID dosing could introduce adherence issues compared with a drug with less frequent dosing.…”

“…31 Compared with prostanoids, selexipag has greater selectivity for the IP receptor, leading to reduced gastrointestinal intolerance, which has been a dose-limiting side effect with oral treprostinil. 32,33 A recent Delphi panel on the use of oral treprostinil suggested aggressive antidiarrheal medication to manage these adverse effects but failed to reach consensus on optimal dosing strategies. 34 In FREEDOM-EV, oral Fig.…”

Pharmacogenomics in the Management of Pulmonary Arterial Hypertension: Current Perspectives

“…[30][31][32][33] Clinical outcomes are most optimal in those patients who can attain higher doses and remain on therapy long term; however, many develop intractable adverse effects (eg, gastrointestinal) or require a switch to other formulations. [33][34][35][36] This study evaluated 15 patients who were newly started on oral treprostinil and those who switched from other treprostinil formulations (intravenous, subcutaneous, or inhaled). Variants in CYP2C8, CYP2C9, and ABCC4 were associated with treatment persistence (defined as maintenance on medication without discontinuation).…”