Inhaled INS1009 demonstrates localized pulmonary vasodilation activity

Introduction: INS1009 is an inhaled formulation of a treprostinil prodrug in a lipid nanoparticle; treprostinil is currently approved for pulmonary arterial hypertension. Although INS1009 demonstrates prolonged pulmonary vasodilator activity, it is unknown if local activity within the lung contributes to its impact and duration. Objectives: 1) Evaluate the pulmonary vasodilator activity of inhaled INS1009 in rats over 24h and compare its pharmacodynamic activity to the plasma and lung tissue treprostinil (TRE) pharmacokinetics. 2) Compare the pulmonary vasodilator activity of inhaled INS1009 and i.v. infused TRE. Methods: The increase in pulmonary arterial pressure (PAP) induced by the thromboxane mimetic, U46619, was measured in anesthetized rats following nose-only inhalation of INS1009 at pulmonary doses of 0.36, 1.8 and 18 µg/kg at times of Immediate Post Dose (IPD), 6, 12 and 24h after dosing. For i.v. studies, TRE was infused at a rate between 2.5 and 1250 ng/kg/min to achieve target plasma TRE concentrations between 0.1 to 50 ng/mL. Plasma and lung tissue samples were collected to measure TRE concentrations. Results: Treatment with inhaled INS1009 (0.36, 1.8, and 18 µg/kg) inhibited the increase of PAP induced by U46619. Prolonged pulmonary vasodilation was observed. Inhaled INS1009 (0.36 μg/kg) at IPD and 6h produced plasma TRE concentrations of 0.28 and 0.03 ng/ml, respectively. In contrast, i.v. TRE infusion which gives a plasma TRE concentration of 0.83 ng/mL had no effect; TRE inhibited the increase of PAP induced by U46619 at higher plasma concentrations. Conclusions: Inhaled INS1009 demonstrates prolonged pulmonary vasodilation that is due in part to the local activity of TRE within the lung.