(G-262) A Microphysiological Model of Human Lung Airway for Evaluating Permeability and Cellular Uptake of Inhaled Drugs

Introduction:: Systemic plasma concentrations are generally analyzed for the evaluation of inhaled drugs without providing enough information about how drugs penetrate lung tissues. Cellular in vitro models have limitations in replicating the structure and function of human lungs and thus do not robustly estimate clinical drug dissolution in the lung epithelium and airway drug permeability. Microphysiological systems (MPS), which mimic the structure and function of human tissues and organs in a laboratory setting, are gaining attention as an alternative to traditional models. We evaluated an MPS-based human lung airway model to determine its effectiveness in estimating the dissolution and permeability of two inhaled drugs: fluticasone furoate (FF) and albuterol sulfate (AS).

Materials and Methods:: The airway model was generated by co-culturing primary human lung bronchial epithelial and microvascular endothelial cells (Figure 1A). The model was characterized by evaluating parameters such as cell confluency, cell-type composition, ciliation, tight junctions, mucus layer formation, transepithelial electrical resistance (TEER), and barrier function using FITC-dextran. The intracellular and extracellular concentrations of drugs were measured using LC-MS/MS.

Results, Conclusions, and Discussions:: Primary human lung cells grown in an air-liquid interface and fluid flow allowed recapitulation of human-specific lung structure and function e.g., 3D structure, multicellular composition (Figure 1B), cilia beating, intercellular tight junctions, mucus secretion, and barrier integrity measured by TEER and low amount of dextran permeability. Due to high lipophilicity of FF (logP: 4.13), we observed significant intracellular concentrations for epithelial and endothelial cells (Figure 1C). However, we also observed a loss of 72-92% of FF due to non-specific bindings (NSB), which affected the permeability of FF across the epithelial barrier (Figure 1D). The results of AS demonstrated an apparent permeability of ~7×10-6 cm/s but very low intracellular concentrations (< 1% cellular uptake) (Figure 1C and 1D). NSB was not observed for AS due to its high water solubility and low lipophilicity (logP: 0.44). Overall, the airway model demonstrated potential as a screening tool for drugs that have similar physiochemical properties to AS. However, the model may have limitations in predicting the lung dissolution and permeability of inhaled drugs with similar physicochemical properties to FF (low water solubility and high lipophilicity). Currently, the utility of airway model is being assessed further by evaluating permeability and cellular uptake of additional inhaled drugs e.g., olodaterol hydrochloride and formoterol fumarate. The data/results of this study could be used in the development of a draft guidance on MPS performance standards and quality control criteria.

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