Exercise Tolerance in PAH Increased With Thrice-Daily Oral Treprostinil

Pulmonary Hypertension Chest Illustration
Pulmonary Hypertension Chest Illustration
This pharmacokinetic substudy was conducted to determine the actual pharmacokinetic profiles of treprostinil in patients transitioning from stable twice daily to stable thrice daily dosing regimens.

Thrice-daily dosing of oral treprostinil in pulmonary arterial hypertension (PAH) has been linked with higher drug trough levels and better long-term tolerability, according to research published in Pulmonary Circulation.

Researchers conducted an open-label extension study (FREEDOM-EXT; ClinicalTrials.gov identifier: NCT01027949) of participants who completed the phase 2 or phase 3 parent studies (ClinicalTrials.gov identifier: NCT01104870, NCT01477333, NCT01588405, NCT00325442, NCT00887978, and NCT00325403) to examine the safety and efficacy of thrice-daily oral treprostinil in patients with PAH.

Participant data were collected between January 2007 and September 2015. Dosing and safety visits were conducted at baseline, 6 months, 12 months, and yearly until discontinuation. Each visit assessed clinical laboratory parameters, study drug dosing, adverse events, and concomitant PAH medications, as well as 6-Minute Walk Distance (6MWD) and Borg dyspnea score at month 12.

The total open-label extension cohort included 894 participants. Mean age of participants was 48±15 years, and participants were primarily women (78%); 68% of participants had idiopathic or heritable PAH with a mean time of 2.8±4 years since diagnosis. Mean baseline 6MWD was 351±83 meters.

Thirty-three percent of patients were treatment-naïve at baseline; 39% were being treated with 1 background PAH therapy, and 28% were treated with combination endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy.

Data for 569 participants who completed the month 12 analysis were available. For this group, the median change in 6MWD from baseline to month 12 was 22 m (interquartile range, -14 to 67 m). Participants in this group were allowed to transition from twice to thrice-daily dosing (mean dose 11.2 mg).

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Following this change, the previous most commonly reported adverse events — including nausea, vomiting, diarrhea, and flushing — improved following this transition.

Additionally, researchers found that among 13 participants who transitioned to thrice-daily dosing and who underwent pharmacokinetic measurements both before and after, trough drug levels were higher with increased dosing.

Limitations to the study include the lack of blinding and a control group, due to the open-label, observational nature of the study. Additionally, researchers noted that both N-terminal probrain natriuretic peptide and World Health Organization–functional class assessment would have been “prognostically significant adjuncts to exercise tolerance” that should have also been measured.

“Oral treprostinil is associated with modest but durable, dose-responsive effects on exercise tolerance,” the researchers concluded. “[Thrice-daily] dosing was associated with higher trough levels and better tolerability.”

Disclosure: The original parent studies were funded by United Therapeutics. Multiple authors reported relationships with United Therapeutics. For a complete list of disclosures, please see the full text of the study online.


White RJ, Parikh K, Allen R, et al. Long term study of oral treprostinil to treat pulmonary arterial hypertension: dosing, tolerability, and pharmacokinetics [published online July 10, 2019]. Pulm Circ. doi:10.1177/2045894019866335