Safety, Tolerability, and Pharmacokinetics of Treprostinil Palmitil Inhalation Powder for Pulmonary Hypertension: A Phase 1, Randomized, Double-Blind, Single- and Multiple-Dose Study.

introductionTreprostinil is a prostacyclin vasodilator widely used for the treatment of pulmonary arterial hypertension (PAH) and, in its inhaled form, for pulmonary hypertension associated with interstitial lung disease (PH-ILD). Treprostinil palmitil inhalation powder (TPIP) is a dry powder formulation of treprostinil palmitil (TP), an ester prodrug of treprostinil. TPIP is designed to provide sustained release of treprostinil in the lung over a prolonged period, potentially enabling a once-daily (QD) dosing regimen and significantly higher tolerated doses compared with currently available treprostinil formulations. This phase 1 study assessed the safety, tolerability, and pharmacokinetics of TP and treprostinil following single and multiple QD administrations of TPIP in healthy volunteers.

methodsHealthy adults (aged 18-45 years) were randomized to receive single or multiple QD inhalation doses of TPIP. Participants in the single-dose phase received TPIP 112.5, 225, 450, or 675 µg (n = 6/dose) or placebo (n = 2). Participants in the multiple-dose phase received TPIP 225 µg QD for 7 days (n = 6), 112.5 µg QD for 4 days followed by 225 µg QD for 3 days (n = 6), or placebo for 7 days (n = 4).

resultsOverall, 41 of 42 participants (97.6%) completed the study. In the single-dose phase, 70.8% (n = 17/24) of TPIP-treated participants experienced a treatment-emergent adverse event (TEAE) vs 0% (n = 0/2) of placebo-treated participants; the most common TEAEs (≥ 20%) were cough (45.8%), dizziness (29.2%), and throat irritation (20.8%). In the multiple-dose phase, 83.3% (n = 10/12) of TPIP-treated participants experienced a TEAE vs 50.0% of placebo-treated participants (n = 2/4); the most common TEAEs were cough (58.3% TPIP vs 50.0% placebo), headache (50.0% vs 0%), nausea (33.3% vs 0%), chest discomfort (33.3% vs 0%), and dizziness (25.0% vs 0%). Most TEAEs were mild; only seven patients experienced a moderate TEAE, and no severe or serious TEAEs occurred. In the multiple-dose phase, participants whose doses were titrated from TPIP 112.5 µg QD to 225 µg QD experienced fewer TEAEs than those who received 225 µg QD at treatment initiation (66.7% vs 100.0%), and all TEAEs with dose titration were mild. After a single dose of TPIP, treprostinil elimination t

conclusionTPIP was well tolerated at the doses tested, and dose titration improved tolerability. Treprostinil pharmacokinetics were linear and supportive of a QD treatment regimen. These results support further development of TPIP in patients with PAH and PH-ILD.