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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 3/2015

Open Access 01-03-2015 | Original Research Article

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Nebulized Sodium Nitrite (AIR001) Following Repeat-Dose Inhalation in Healthy Subjects

Authors: Peter J. Rix, Andrew Vick, Neil J. Attkins, Geoffrey E. Barker, Adrian W. Bott, Harry Alcorn Jr., Mark T. Gladwin, Sruti Shiva, Stephen Bradley, Azra Hussaini, William L. Hoye, Ed L. Parsley, Hiroko Masamune

Published in: Clinical Pharmacokinetics | Issue 3/2015

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Abstract

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.
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Metadata
Title
Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Nebulized Sodium Nitrite (AIR001) Following Repeat-Dose Inhalation in Healthy Subjects
Authors
Peter J. Rix
Andrew Vick
Neil J. Attkins
Geoffrey E. Barker
Adrian W. Bott
Harry Alcorn Jr.
Mark T. Gladwin
Sruti Shiva
Stephen Bradley
Azra Hussaini
William L. Hoye
Ed L. Parsley
Hiroko Masamune
Publication date
01-03-2015
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 3/2015
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-014-0201-y

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