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

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.

Figures

Fig. 1

Concentration–time profiles of plasma nitrite relative to the start of a 10-min sodium nitrite inhalation in healthy male and female subjects following a single dose (left) or on day 6 (right) following a total of 16 (every 8 h) administrations in Part A of study CS04. Values represent mean (n = 3 or 6), and error bars represent standard deviation. Dosage levels represent the mass of sodium nitrite loaded into the nebulizer medication chamber. 120-mg dosage level discontinued after day 1 due to DLT in two of three subjects

Fig. 2

Inter-study comparison of dose response for plasma nitrite Cmax and AUCinf (or AUC0–t for cohorts where AUCinf could not be calculated) following a single sodium nitrite inhalation in healthy male and female subjects. Nitrite concentrations in subjects from studies CS01 and CS02 were individually background subtracted prior to calculation of Cmax and AUC, while no correction was used for study CS04 because pre-dose nitrite was below the limit of detection in all subjects (cf Online Resource 1; Table 1). Values represent mean (n = 3–6), and error bars represent standard deviation. AUCinf area under the plasma concentration–time curve from time zero to infinity, AUC0–t area under the plasma concentration-time curve from time zero to last quantifiable, Cmax maximum plasma concentration

Fig. 3

Dose response of Cmax and AUC0–8 h for nitrate metabolite in plasma following single (day 1) or repeated (day 6, after 16 total every 8 h doses) inhalation of sodium nitrite in healthy male and female subjects from Part A of study CS04. Nitrate concentrations in subjects were individually background subtracted prior to calculation of Cmax and AUC. Values represent mean (n = 3 or 6), and error bars represent standard deviation. AUC area under the plasma concentration–time curve, AUC0–8 h area under the plasma concentration–time curve from time zero to 8 h, Cmax maximum plasma concentration

Fig. 4

Fraction exhaled nitric oxide (FENO) in parts per billion (ppb), pre-dose and 5 min after the end of inhalation following single dose (left) or after 16 total every 8 h doses (right) in all sodium nitrite-treated subjects at well-tolerated dosage levels of 15, 45, and 90 mg from Part A of study CS04 (n = 18). p values from paired Student’s t tests of pre- vs. post-dose values on each study day. Mean FENO increased from 16.1 to 68.7 ppb on day 1 (4.3-fold increase) and from 14.8 to 84.3 ppb on day 6 (5.7-fold increase)

Fig. 5

Concentration–time profiles (n = 3 or 6) of S-nitrosothiol (R-SNO) species (upper) and iron-nitrosyl-hemoglobin (lower) in whole blood following a single 10-min inhalation of sodium nitrite in healthy male and female subjects in Part A of study CS04. Values represent mean (n = 3–6), and error bars represent standard deviation. Dosage levels represent the mass of sodium nitrite loaded into the nebulizer medication chamber. FENO fraction exhaled nitric oxide