A test of the same dose of a fine and a coarse aerosol in dog surprisingly indicated negligible intranasal filtration

Mikael Brülls¹, Steven Oag¹ & Eva Lamm Bergström¹

¹ AstraZeneca BioPharmaceuticals R&D, AstraZeneca R&D Gothenburg, Mölndal, SE-431 83, Sweden

Summary

A novel inhalation exposure system was developed to increase the efficiency of pharmacokinetic (PK) evaluations of inhaled drugs in a large species such as the dog by enabling simultaneous administration of multiple drugs to the same animal in a single experiment, facilitating a direct comparison of the same lung dose of different drugs using the same blood samples, which can be considered to be a refinement measure from an animal research perspective.

When validating the system in vivo, which included a comparison of the same nebulized dose of a fine and coarse aerosol, no detectable difference in lung deposited dose was observed. We expected the aerosol droplet size to have an impact and were surprised by the results, which indicated negligible intranasal filtration.

The intentionally extremely poorly soluble drugs selected for this study were developed for local treatment of the lung via inhalation. The three drugs were known to have low oral bioavailability and expected to also have low nasal bioavailability, because it has been shown [1-3] that drugs such as mometasone furoate, fluticasone propionate and fluticasone furoate have low nasal bioavailability (<1%) due to poor solubility. The solubilities of the selected drugs are as low or even lower than the mentioned drugs. It was thus expected that the systemic exposure would be derived primarily from pulmonary absorption. This facilitated the determination of the lung deposited dose by a PK assessment.

This finding disproves the assumption that a mouth tube is required in dog studies to eliminate the high filtration that is believed to occur during nasal inhalation.  The option of using nasal breathing instead of a mouth tube in dog studies is less invasive and considered a refinement measure from an animal research perspective.

Key Message

The study finding is important considering that devices for oropharyngeal delivery in dogs are applied to eliminate the high intranasal filtration assumed to be occurring during nasal breathing. Oropharyngeal dosing is more invasive than oronasal dosing and avoiding that method is considered a refinement measure from an animal research perspective.