title: Lung Deposition of Alpha1-Proteinase Inhibitor (Human) (A1-PI[H]) Inhalation Solution Using Two Inhalation Modes of the I-neb Adaptive Aerosol Delivery (AAD) System in Healthy Subjects and Subjects with Cystic Fibrosis.
abstract: In cystic fibrosis (CF) patients, inhalation of alpha1-proteinase inhibitor (A1-PI) can prevent or slow down persistent infections and reduce the massive ongoing inflammation and excessive levels of NE that destroy the airway epithelium, leading to progressive loss of pulmonary function and death. It is essential for an efficient treatment with inhaled A1-PI that an adequate and reproducible dose is deposited within all regions of the lung. The I-neb AAD System provides two inhalation modes: the Target Inhalation Mode (TIM) and the Tidal Breathing Mode (TBM). Both were compared in this study for their efficiency to deliver A1-PI to the lungs.
  
  
  
  This was a randomized, open label, cross-over study to investigate the lung deposition of A1-PI in 6 healthy subjects (HS) and 15 CF subjects. The primary endpoint was to evaluate the total lung deposition relative to filling dose of A1-PI inhalation solution using the I-neb AAD System in TIM and in TBM. The main secondary endpoints were extra-thoracic deposition, exhaled drug fraction, nebulizer residue, C/P ratio, and variance of pixel counts. Additional exploratory endpoints were total treatment time and the inhalation time. Radiolabeling was performed considering GMP using a commercially available sterile labeling kit. Radiolabeling was validated using NGI data acquired by gamma scintillation and UV spectrometry.
  
  
  
  The intrapulmonary deposition (mean ± SD) in CF subjects was 47.0% ± 6.6% and 46.7% ± 10.3% in TIM and TBM, respectively, and in healthy subjects, 50.0% ± 6.7% and 54.8% ± 7.0% in TIM and TBM, respectively. TIM resulted in an approximately 40% lower treatment time (HS 6.4 min vs. 10.3 min, CF 5.3 min vs. 10.7 min) and less extra-thoracic deposition compared to TBM, and showed a higher residue of drug in the nebulizer, compared to TBM. In both groups, inhalation of a single dose of 77 mg of A1-PI was efficient, safe, and well tolerated using TIM and TBM.
authors.affiliation: 1 Inamed GmbH , Gauting, Germany .
authors.forename: Sabine
authors.initials: S
authors.lastname: Häussermann
authors.affiliation: 2 CSL Behring AG , Bern, Switzerland .
authors.forename: Cornelis
authors.initials: C
authors.lastname: Winnips
authors.affiliation: 3 CSL Behring LLC , King of Prussia, Pennsylvania.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Edelman
authors.affiliation: 1 Inamed GmbH , Gauting, Germany .
authors.forename: Dominik
authors.initials: D
authors.lastname: Kappeler
authors.affiliation: 1 Inamed GmbH , Gauting, Germany .
authors.forename: Christiane
authors.initials: C
authors.lastname: Herpich
authors.affiliation: 1 Inamed GmbH , Gauting, Germany .
authors.forename: Hilke
authors.initials: H
authors.lastname: Ehlich
authors.affiliation: 1 Inamed GmbH , Gauting, Germany .
authors.forename: Daniela
authors.initials: D
authors.lastname: Zanker
authors.affiliation: 1 Inamed GmbH , Gauting, Germany .
authors.forename: Claudius
authors.initials: C
authors.lastname: Kietzig
authors.affiliation: 1 Inamed GmbH , Gauting, Germany .
authors.forename: Knut
authors.initials: K
authors.lastname: Sommerer
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000336:Aerosols; D000465:Algorithms; D000890:Anti-Infective Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016503:Drug Delivery Systems / Q000295:instrumentation*; D004867:Equipment Design; D005260:Female; D005858:Germany; D006801:Humans; D001239:Inhalation; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008954:Models, Biological; D009330:Nebulizers and Vaporizers; D014018:Tissue Distribution; D055815:Young Adult; D000515:alpha 1-Antitrypsin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000336:Aerosols; D000890:Anti-Infective Agents; D000893:Anti-Inflammatory Agents; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin
keywords: I-neb AAD System; alpha-1-antitrypsin; alpha1-proteinase inhibitor; cystic fibrosis; inhaled drug; lung deposition; lung imaging; nebulizer; pulmonary function testing; scintigraphy