A physiologically based pharmacokinetic model of human airway epithelia

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Abstract Inhaled drugs represent an important, effective, but often expensive therapeutic option for lung diseases such as asthma or chronic obstructive pulmonary disease (COPD). Development of generic equivalents to brand name inhaled drugs could reduce the financial burden associated with these agents but is limited by difficulties performing pharmacokinetic (PK) bioequivalence studies on airway epithelia, the primary target of inhaled agents. Although physiologically based pharmacokinetic (PBPK) models can serve as an alternative to direct measurement of drug PK within airway epithelia, current models fail to account for the actions of drug transporters and metabolizing enzymes that may influence the effective concentrations of inhaled drugs. To address this gap, we have assembled a group of experts on airway epithelial cell culture, quantitative proteomics, PBPK modeling, and PK testing of aerosolized drugs to systematically measure the protein levels of relevant drug transporters and metabolizing enzymes within human airway epithelia. Our proposal takes advantage of the robust Tissue Procurement and Cell Culture Core present at our institution that can provide us with primary human airway epithelial cells for culture representing a wide range of demographic factors and anatomic locations as well as in vivo tissue samples for testing. Our plan is to develop a comprehensive assessment of the drug transporters and metabolizing enzymes present in airway epithelia based on literature review and analysis of our own existing RNA sequencing databases, then utilize this data to develop quantitative targeted absolute proteomic (QTAP) methods for measurement of the relevant proteins. This QTAP methodology will then be applied to human airway epithelia representing a wide range of demographic features, anatomic locations, and inflammatory states as well as tissues obtained in vivo. Ultimately, we will utilize this data to develop enhanced PBPK models, which we will then test be tested via mass spectrometric analysis of test drug and drug metabolites in apical, intracellular, and basolateral compartments after aerosolization onto airway epithelia. Overall, the studies in this proposal will generate a comprehensive evaluation of the levels of drug transporters and metabolizing enzymes in human airway epithelia and enhanced PBPK modeling that can support more rapid development of generic versions of inhaled drugs.