title: Pharmacokinetics, pharmacodynamics, safety, and tolerability of nebulized sodium nitrite (AIR001) following repeat-dose inhalation in healthy subjects.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  On the basis of these results, nebulized sodium nitrite (AIR001) has been advanced into randomized trials in PAH patients.
authors.affiliation: Seragon Pharmaceuticals, Inc., 12780 El Camino Real, San Diego, CA, 92130, USA, peter.rix@seragonpharm.com.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Rix
authors.forename: Andrew
authors.initials: A
authors.lastname: Vick
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Attkins
authors.forename: Geoffrey E
authors.initials: GE
authors.lastname: Barker
authors.forename: Adrian W
authors.initials: AW
authors.lastname: Bott
authors.forename: Harry
authors.initials: H
authors.lastname: Alcorn
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
authors.forename: Sruti
authors.initials: S
authors.lastname: Shiva
authors.forename: Stephen
authors.initials: S
authors.lastname: Bradley
authors.forename: Azra
authors.initials: A
authors.lastname: Hussaini
authors.forename: William L
authors.initials: WL
authors.lastname: Hoye
authors.forename: Ed L
authors.initials: EL
authors.lastname: Parsley
authors.forename: Hiroko
authors.initials: H
authors.lastname: Masamune
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D015331:Cohort Studies; D004347:Drug Interactions; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage; D011687:Purines / Q000008:administration & dosage; D000068677:Sildenafil Citrate; D012977:Sodium Nitrite / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D013449:Sulfonamides / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D015415:Biomarkers; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D012977:Sodium Nitrite