Assessment of Inhaled Treprostinil Palmitil, Inhaled and Intravenous Treprostinil, and Oral Selexipag in a Sugen/Hypoxia Rat Model of Pulmonary Arterial Hypertension

Abstract

Treprostinil palmitil (TP), a long-acting inhaled pulmonary vasodilator prodrug of treprostinil (TRE), has beneficial effects in a Sugen5416/Hypoxia (Su/Hx) rat model of pulmonary arterial hypertension (PAH) that compare favorably to the oral PDE5 inhibitor, sildenafil. In this study in male Sprague Dawley rats, a dry powder formulation of TP (TPIP) was compared to inhaled and intravenous TRE and oral selexipag to evaluate inhibition of hemodynamic and pathological changes in the lungs and heart induced by Su/Hx challenge. Su (20 mg/kg) was injected subcutaneously followed by 3 weeks of Hx (10% O 2 /balance N 2 ), then initiation of test article administration over 5 weeks with room air breathing. Hemodynamics and histopathology were measured at the end of the study. Su/Hx challenge approximately doubled the mean pulmonary arterial blood pressure (mPAP) and the Fulton index, decreased cardiac output (CO), doubled the wall thickness and muscularization of the small (10-50 μm) and medium (51-100 μm) sized pulmonary arteries and increased the percentage of obliterated pulmonary blood vessels. Even though inhaled TRE (65 μg/kg, QID), intravenous TRE (810 ng/kg/min) and oral selexipag (30 mg/kg, BID) provided some beneficial effects against the Su/Hx challenge, the overall benefit was generally greater with TPIP at high dose (117 μg/kg, QD). These results demonstrate that TPIP compares favorably to inhaled and intravenous TRE and oral selexipag with respect to inhibition of the pathophysiological changes induced by Su/Hx challenge in rats.

Therapeutic Potential of Treprostinil Inhalation Powder for Patients with Pulmonary Arterial Hypertension: Evidence to Date

“… 34 Two studies conducted using the Sugen/hypoxia rat model of PAH compared the hemodynamic effects of TPIP with other vasodilators – oral sildenafil in the first, and intravenous and inhaled treprostinil and oral selexipag in the second. 35 , 36 These studies found at least equivalent efficacy in hemodynamic improvements in Su/Hx rats when comparing TPIP to established pulmonary vasodilators. Additionally, trials in animal models have suggested a higher cough threshold than conventional inhaled treprostinil, promising improved tolerance by reducing one of the drug’s principal adverse effects.…”

Unraveling the Lung Vascular Remodeling in Pulmonary Hypertension Using a Quantitative Digital Pathology Software

“…For the conventional evaluation of the lung vascular remodeling, H&E-stained sections were scanned at 40X and used as described previously (17). Briefly, the pulmonary arteries/arterioles visualized from about 20 random fields of view were identified and categorized according to their Feret diameter into small (10–50 µm), medium (51–100 µm), and large diameter vessels (>100 µm); and the percentage of these pulmonary blood vessels demonstrating the presence of a muscular (completely surrounded by a smooth muscle layer, > 90% circumference), semi-muscular (incompletely surrounded by a smooth muscle layer, 10 – 90% circumference) or a non-muscular (no apparent smooth muscle layer, < 10% circumference) appearance were quantified.…”

“…Conventional assessment of vessel morphometry consists of visually selecting a limited number of fields of view from H&E-or elastin-stained lung sections in order to manually identify blood vessels (generally up to 50) and to measure the vascular wall thickness for each vessel (2 measurements/vessel). Other also uses a-smooth muscle actin (a-SMA) labelled sections to focus on the medial hypertrophy (16,17). Additional limitations include a global analysis of endothelial cell and/or muscle cell proliferation, as well as the exclusion of blood vessels of irregular shape (non-circular).…”