Calendar | For Your Patients | PHA Main Site | Contact Us | About Us | Not a registered user? Sign up here.

Resource Library

Novel Analysis of Treprostinil Dose-Response Relationship Using Weight-Normalized Dosing

Gautam Ramani

E Shen

Meredith Broderick

A Wasik

Y Rao


  Sign in to add a review

Leave a Comment

Conference: 2018 PHA International PH Conference & Scientific Sessions

Release Date: 06.28.2018

Presentation Type: Abstracts

File Download: Conference 2018_1053

Download Adobe Acrobat

2018 International PH Conference and Scientific SeAbstract presented at the 2018 International PH Conference and Scientific Sessions in Orlando, Fla., June 28-July 1, 2018.


Treprostinil is a prostacyclin analogue available in intravenous, subcutaneous (SC), inhaled, and oral administration routes for pulmonary arterial hypertension (PAH). Doses are titrated based on tolerability and clinical response. Because doses are individualized, conventional dose-response studies using randomized drug exposure are difficult to employ. In this novel analysis, we report outcomes with weight-normalized doses to SC and oral treprostinil.


Data from patients receiving treatment in the pivotal SC treprostinil study were combined with the FREEDOM-M study of oral treprostinil. To facilitate pooling of dosing data, oral doses were converted to weight-based, continuous doses (ng/kg/min), accounting for patient weight and bioavailability. Patients were grouped into dose tertiles, based on doses achieved at week 12 in the clinical studies. Last observation carried forward (LOCF) was used to impute last observations of 6MWD, Borg dyspnea score (BDS), World Health Organization (WHO) functional class (FC), and dose. One-way analysis of variance (ANOVA) and Jonckheere-Terpstra tests were used to assess differences and linear trends in 6MWD, WHO FC, and Borg dyspnea score.


466 patients were included in this analysis (SC, N=233; oral, N=233). The mean SC and oral treprostinil dose at week 12 was 9.3 ng/kg/min and 13.8 ng/kg/min, respectively. There were differences in baseline characteristics (age, weight, PAH duration) between dose tertiles. Median doses in the low (N=151), medium (N=159), and high dose (N=156) tertiles were 3.7, 9.1, and 18.5 ng/kg/min respectively and median 6MWD improvements were 13, 22, and 30 meters, respectively. There was a statistically significant difference in 6MWD improvement between low/high groups (p=0.013) and a statistically significant linear trend for 6MWD improvement with higher doses (p=0.0052). Significant differences in Borg dyspnea score was observed between the low/medium groups (p=0.007) and low/high groups (p<0.001) with median improvements of 0.0, 1.0, and 1.0 in the low, medium, and high groups, respectively. WHO FC improvement were not significantly different between dose groups


This combined analysis of SC and oral treprostinil provides evidence for the dose-response relationship of treprostinil. Increased treprostinil dose is associated with improvements in 6MWD and Borg dyspnea score. Although these improvements are relatively modest, treprostinil doses used in both studies are low compared to those routinely used in clinical practice. Results from this novel post-hoc analysis suggest that systemically administered treprostinil, in oral or SC formulations, produces statistically significant, dose-dependent therapeutic responses.

Change in Exercise Capacity by Treprostinil Dose