Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction.

BACKGROUND: Pulmonary hypertension (PH) is associated with poor outcomes, yet specific treatments only exist for a small subset of patients. The most common form of PH is that associated with left heart disease (Group 2), for which there is no approved therapy. Nitrite has shown efficacy in preclinical animal models of Group 1 and 2 PH, as well as in patients with left heart failure with preserved ejection fraction (HFpEF). We evaluated the safety and efficacy of a potentially novel inhaled formulation of nitrite in PH-HFpEF patients as compared with Group 1 and 3 PH. METHODS: Cardiopulmonary hemodynamics were recorded after acute administration of inhaled nitrite at 2 doses, 45 and 90 mg. Safety endpoints included change in systemic blood pressure and methemoglobin levels. Responses were also compared with those administered inhaled nitric oxide. RESULTS: Thirty-six patients were enrolled (10 PH-HFpEF, 20 Group 1 pulmonary arterial hypertension patients on background PH-specific therapy, and 6 Group 3 PH). Drug administration was well tolerated. Nitrite inhalation significantly lowered pulmonary, right atrial, and pulmonary capillary wedge pressures, most pronounced in patients with PH-HFpEF. There was a modest decrease in cardiac output and systemic blood pressure. Pulmonary vascular resistance decreased only in Group 3 PH patients. There was substantial increase in pulmonary artery compliance, most pronounced in patients with PH-HFpEF. CONCLUSIONS: Inhaled nitrite is safe in PH patients and may be efficacious in PH-HFpEF and Group 3 PH primarily via improvements in left and right ventricular filling pressures and pulmonary artery compliance. The lack of change in pulmonary vascular resistance likely may limit efficacy for Group 1 patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01431313 FUNDING. This work was supported in part by the NIH grants P01HL103455 (to MAS and MTG), R01HL098032 (to MTG), and R01HL096973 (to MTG), and Mast Therapeutics, Inc.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of nebulized sodium nitrite (AIR001) following repeat-dose inhalation in healthy subjects.

INTRODUCTION: The efficacy of nebulized sodium nitrite (AIR001) has been demonstrated in animal models of pulmonary arterial hypertension (PAH), but it was not known if inhaled nitrite would be well tolerated in human subjects at exposure levels associated with efficacy in these models. METHODS: Inhaled nebulized sodium nitrite was assessed in three independent studies in a total of 82 healthy male and female subjects. Study objectives included determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) under normal and mildly hypoxic conditions, and following co-administration with steady-state sildenafil, assessment of nitrite pharmacokinetics, and evaluation of the fraction exhaled nitric oxide (FENO) and concentrations of iron-nitrosyl hemoglobin (Hb(Fe)-NO) and S-nitrosothiols (R-SNO) as biomarkers of local and systemic NO exposure, respectively. RESULTS: Nebulized sodium nitrite was well tolerated following 6 days of every 8 h administration up to 90 mg, producing significant increases in circulating Hb(Fe)-NO, R-SNO, and FENO. Pulmonary absorption of nitrite was rapid and complete, and plasma exposure dose was proportional through the MTD dosage level of 90 mg, without accumulation following repeated inhalation. At higher dosage levels, DLTs were orthostasis (observed at 120 mg) and hypotension with tachycardia (at 176 mg), but venous methemoglobin did not exceed 3.0 % at any time in any subject. Neither the tolerability nor pharmacokinetics of nitrite was impacted by conditions of mild hypoxia, or co-administration with sildenafil, supporting the safe use of inhaled nitrite in the clinical setting of PAH. CONCLUSION: On the basis of these results, nebulized sodium nitrite (AIR001) has been advanced into randomized trials in PAH patients.