Assessment of inhaled medications using an in vitro human alveolar microphysiological system.

Abstract

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. Global prevalence of COPD ranges from 7-19%, with higher incidences in low- and middle- income countries. It is predicted that COPD will become the leading cause of death in the future. Hence it is crucial that better preclinical models are developed to analyse new therapeutics more effectively and rapidly.

A microphysiological system (MPS) human alveolar in vitro model has been developed for this application. It can be used to understand predict the absorption of inhaled medications in the alveoli and permeability through to the circulatory system. The system uses perfused media and air-liquid interphase conditions which causes human primary cells to produce physiologically relevant tissues. An open well insert format allows addition of stimuli and application of compounds to either side of the culture. Here, a coculture of epithelial and endothelial cells were used to assess inhaled medications for COPD.

The permeability and absorption of three distinct inhaled medications were compared. Salbutamol, olodaterol and fluticasone were applied in small-volume liquid doses to the apical side of the insert and measured over time. Salbutamol permeated through the tissue and into the basolateral side quicker than the more lipophilic compounds, which were retained in the epithelial cell compartment. This is consistent with clinical data that shows higher retention, and therefore longer lasting effects, of these drugs in lung tissue. The alveolar MPS was predictive of compound dynamics in the lung and will be used to analyse pharmacology and toxicity of inhaled compounds in future studies.