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

Abstract

Introduction: Treprostinil 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.

Methods: Healthy 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).

Results: Overall, 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 t1/2 was 8.67-11.6 h and exposure was dose proportional, with mean (CV%) Cmax 78.4-717 pg/mL (38.6-72.9%) and AUC0-∞ 1090-5480 pg·h/mL (11.5-30.0%). At steady state (TPIP 225 µg), the mean (CV%) of Cmax, Cmin, and AUCτ were 193-228 pg/mL (32.9-46.4%), 17.6-22.8 ng/mL (43.7-64.4%), and 1680-1820 pg·h/mL (28.7-36.6%), respectively. The elimination t1/2 was 6.84-8.82 h after repeat dosing. No steady-state accumulation was observed. Plasma concentrations of TP were below the limit of quantification (100 pg/mL) at all time points measured.

Conclusion: TPIP 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.

Keywords: Interstitial lung disease; Pharmacokinetics; Phase 1 study; Pulmonary arterial hypertension; Pulmonary hypertension; Treprostinil; Treprostinil palmitil inhalation powder.

© 2022. The Author(s).

Figures

Fig. 1

Study design. All doses were administered using 112.5-μg single-actuation capsules. d day, PK pharmacokinetics, QD once daily, Scn screening, TPIP treprostinil palmitil inhalation powder. aBlood samples for PK assessments in the single-dose phase were collected within 15 min before dosing and at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 24 (day 2), 36 (day 2), 48 (day 3), and 72 (day 4) hours after administration of TPIP or placebo; blood samples for PK assessments in the multiple-dose phase were collected within 30 min before dosing and at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 10, and 12 h after dosing on day 1, before dosing only on days 2, 3, 4, 5, and 6, and before dosing on day 7 and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 24 (day 8), 48 (day 9), and 72 (day 10) hours after day 7 dosing

Fig. 2

Treprostinil plasma concentration in healthy participants following a single TPIP dosing or b multiple QD TPIP dosing (PK population). d day, PK pharmacokinetics, QD once daily, TPIP treprostinil palmitil inhalation powder. aPre-dose samples were collected all days; serial post-dose samples were only collected on days 1 and 7