Perspectives on Lung Dose and Inhaled Biomolecules

Abstract

Dose is highly important to studies of inhaled agents because there must be an understanding of the dose delivered to humans, the dose delivered to animals in toxicology studies, and an ability to interpret and compare both sets of information relative to safety. Unlike oral or intravenous administrations, total delivered or inhaled dose is not easy to determine following inhalation exposure and is also not necessarily the most important determinant of toxicity. A review of dose distribution throughout the respiratory tract as well as total inhaled dose is provided. The implications of regional deposition for biologics are reviewed and specific examples over a range of different molecular weights are provided. Biologics are generally large enough that absorption from ciliated epithelia is low. Thus, deposition of biologics in head airways and tracheobronchial regions is unlikely to be of high importance unless there are interactions with specific receptors at these sites. Therefore, it is the dose of proteins or biologics deposited in the alveolar region that are generally of most interest.

Structure-Function Relationships Of Mucociliary Clearance In Human Airways

“…Furthermore, mouse airways diverge from human airways in other relevant aspects, including near 100-fold smaller spatial dimensions, a different branching morphology, and the absence of mucus-producing goblet cells in healthy conditions 59 , similar to our findings in rats. Additionally, the deposition of inhaled particle deposition differs between humans and obligatory nose breathers like rats and mice 60,61 . Consequently, MCC may operate under different constraints in humans and other larger animals compared to rodents.…”

Protein Aggregates in Inhaled Biologics: Challenges and Considerations

“…The upper airways are lined with thick mucus layer and beating cilia for mucociliary clearance, making biologics less efficacious in this region. The alveolar region provides a huge surface area with thin layer of lining fluid abundant with immune cells, such as alveolar macrophages, making it the main area for immunogenicity risks 35 . It is possible that any formed insoluble protein aggregates in the lungs would be rapidly cleared by alveolar macrophages.…”

“…Unlike the lyophilized products, which are reconstituted to achieve a predefined concentration prior to administration 49 , a range of drug concentrations are expected along the respiratory tract due to its complex anatomy and based on the aerodynamic diameter of the drug particles which dictates the product deposition profile after inhalation 50 , 51 . The risk of protein aggregation in the lungs may be dependent on the inhaled dose, dosing frequency 52 and site of deposition 35 , which poses significant complexity on setting up the ALI culture studies to mimic the in vivo conditions.…”

Structure-function relationships of mucociliary clearance in the human airways

“…This prompts the question whether MCC operates under distinct constraints in humans and larger animals versus rodents. Variation in inhaled particle deposition levels and sizes exists between human and rodent airways 56 . Obligatory nose breathers like rats and mice mainly clear particles in the nasal passages, whereas in humans, absorption primarily occurs in the large airways 57 .…”