Safety and pharmacokinetics study of a single ascending dose of C16TR for inhalation (INS1009)

Background: Inhaled treprostinil (TRE [Tyvaso®]), a vasodilator for pulmonary arterial hypertension (PAH), must be administered QID and is associated with cough. C16TR for Inhalation (INS1009) is a lipid nanoparticle formulation of treprostinil prodrug (hexadecyltreprostinil) that is being developed to provide QD dosing for PAH. C16TR is converted to free treprostinil and hexadecanol. Preclinical studies demonstrated that single-dose inhalation with C16TR is well tolerated and produces long-acting pulmonary vasodilation and sustained levels of treprostinil in plasma and C16TR in lungs. Objectives: First-in-human study of C16TR to determine the PK of free treprostinil and C16TR in healthy volunteers. Methods: The first cohort of 8 subjects received single-dose open-label TRE 54 µg, and was then randomized 3:1 (double-blinded) to single-dose C16TR 85 µg or placebo. The next 4 cohorts were to be randomized 2:1 to single-dose C16TR at 170, 340, 510, 765 µg, or placebo. Results: 24 subjects received C16TR, 85 µg, 170 µg or 340 µg. The PK profiles were qualitatively similar. Cmax was attained within 1 hr and sustained for approx. 8 hr. The mean C max (mg/L) was 0.0976, 0.146, and 0.333, respectively. The mean AUC 0-24 (µg*h /L) was 0.634, 1.24, and 2.19 for the 85 mg, 170 mg, and 340 mg cohorts, respectively. Dose escalation was halted due to observed AE profile in the third cohort. Conclusions: Concentration-time profile demonstrated pharmacokinetic characteristics which could produce sustained effect. Trepostinil systemic exposure as assessed by C max and AUC increased with increasing dose in an approximately dose proportionate manner. In general, AEs were similar to other inhaled prostanoids.