Physical properties, lung deposition modeling, and bioactivity of recombinant GM-CSF aerosolised with a highly efficient nebulizer

Abstract

Pulmonary alveolar proteinosis (PAP) is a rare condition characterized by the accumulation of lipoproteinaceous material within air spaces. Although whole lung lavage is the current standard of care, recent advances in our understanding of PAP pathophysiology suggest that the disorder may benefit from inhalation of recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF). The aim of this study was to determine the physical properties and bioactivity of rGM-CSF aerosolized by the highly efficient AKITA² APIXNEB® nebulizer system. The physical properties of aerosolised rGM-CSF were investigated in terms of droplet size, output and output rate by laser diffraction and gravimetrical analysis. Lung deposition was assessed using deposition modeling (ICRP). Molecular mass before and after aerosolisation was determined by SDS-PAGE, while the bioactivity of rGM-CSF was evaluated by measuring the GM-CSF-stimulated increase in pSTAT-5 using mAM-hGM-R cells. Ninety-six % of the rGM-CSF filling dose was aerosolized with the Akita 2 Apixneb® nebulizer system. Particle size was highly reproducible, and the amount deposited within the lung was 80.35% of the delivered dose. The aerosolisation did not alter the molecular structure of rGM-CSF, nor its ability to stimulate the pSTAT-5, which increased by 99.5%, similar to values for rGM-CSF prior to aerosolisation. We conclude that the highly efficient AKITA² APIXNEB® nebulizer system is likely to efficaciously deliver rGM-CSF to the airways of patients with autoimmune PAP.

Inhaled GM-CSF in a Pulmonary Alveolar Proteinosis Patient Refractory to Plasmapheresis Combined with Multiple Whole Lung Lavages

“…In an apparatus which combines a vibrating mesh nebulizer with a computerized compressor controlling both inhalation fl ow rate and inhaled volume [13]. A 12 weeks acute phase (daily single dose of 250 mcg, for 5 days per week) was followed by a 6 months chronic phase (250 mcg/day on 2 consecutive days every 2 weeks), which started one month after the end of the acute phase.…”

Aerosolized Medications for Gene and Peptide Therapy

“…A previous report by Luisetti et al 127 showed that the AKITA2 APIXNEB nebulizer system aerosolized 96% of a recombinant GM-CSF filling dose, and based on the International Commission on Radiological Protection (ICRP) deposition models, it was predicted that 80.4% of the filling dose would deposit in the lungs. No studies have been performed that compare the AKITA2 APIXNEB nebulizer system and the PARI LC Plus nebulizer used in the previous studies to treat pulmonary alveolar proteinosis.…”

Assessing New Technologies in Aerosol Medicine: Strengths and Limitations

“…49 These were also the operating principles of the AKITA JET and AKITA2 APIXNEB (Vectura, Wilshire, United Kingdom). 49,50 The system has a 4-mL reservoir and allows targeting of peripheral or central airways by modifying the time of release of the aerosol during the inspiratory phase. Aerosol release at the beginning of the inhalation will result in more distal deposition, whereas release in the middle of the inhalation will result in more central deposition.…”