Single dose pharmacokinetics of C16TR for Inhalation (INS1009) vs treprostinil inhalation solution

Background: Inhaled treprostinil (TRE [Tyvaso ® ]) is a QID vasodilator indicated for pulmonary arterial hypertension (PAH). C16TR for Inhalation (INS1009) is a lipid nanoparticle formulation of treprostinil prodrug (hexadecyltreprostinil), under development to provide QD or BID dosing for PAH. C16TR is converted to free treprostinil and hexadecanol. Animal studies found that single-dose inhalation of C16TR resulted in sustained levels of treprostinil in plasma and C16TR in lungs. Objectives: First-in-human study of C16TR to determine the MTD of a single dose and characterize the PK of free treprostinil and C16TR in healthy volunteers. Methods: The first cohort of 8 subjects received single-dose open-label TRE 54µg, and were then randomized 3:1 (double-blinded) to receive a single-dose of C16TR at 85µg or placebo (85 µg of C16TR has an equivalent amount of treprostinil as 54µg of TRE). Results: Cmax values of treprostinil were higher after TRE dosing than after C16TR (TRE:C16TR median, 12.0 [range, 4.25-21.3]). AUC 0-24 was lower (approx. 30%) for C16TR (TRE:C16TR median, 1.32 [range, 1.03-2.18]). Treprostinil AUC profiles were flatter after C16TR treatment, and T max occurred later (median, 1 h vs 0.25 h for TRE). The plasma half-life of treprostinil after C16TR was muchlonger (median, 6.4 h vs 0.6 h for TRE). Conclusion: The longer half-life of treprostinil after C16TR administration was likely due to sustained pulmonary release, consistent with preclinical studies of C16TR. Compared to TRE (54µg), C16TR (85ug) resulted in a 12 times lower plasma C max of treprostinil. The overall exposure to treprostinil was only 30% lower. The AEs in this cohort were similar to other inhaled prostanoids.