In vitro screening for pharmacological activity of existing drugs showed chloroquine and hydroxychloroquine to be effective against severe acute respiratory syndrome coronavirus 2. Oral administration of these compounds to obtain desired pulmonary exposures resulted in dose-limiting systemic toxicity in humans. However, pulmonary drug delivery enables direct and rapid administration to obtain higher local tissue concentrations in target tissue. In this work, inhalable formulations for thermal aerosolization of chloroquine and hydroxychloroquine were developed, and their physicochemical properties were characterized. Thermal aerosolization of 40 mg/mL chloroquine and 100 mg/mL hydroxychloroquine formulations delivered respirable aerosol particle sizes with 0.15 and 0.33 mg per 55 mL puff, respectively. In vitro toxicity was evaluated by exposing primary human bronchial epithelial cells to aerosol generated from Vitrocell. An in vitro exposure to 7.24 μg of chloroquine or 7.99 μg hydroxychloroquine showed no significant changes in cilia beating, transepithelial electrical resistance, and cell viability. The pharmacokinetics of inhaled aerosols was predicted by developing a physiologically based pharmacokinetic model that included a detailed species-specific respiratory tract physiology and lysosomal trapping. Based on the model predictions, inhaling emitted doses comprising 1.5 mg of chloroquine or 3.3 mg hydroxychloroquine three times a day may yield therapeutically effective concentrations in the lung. Inhalation of higher doses further increased effective concentrations in the lung while maintaining lower systemic concentrations. Given the theoretically favorable risk/benefit ratio, the clinical significance for pulmonary delivery of aerosolized chloroquine and hydroxychloroquine to treat COVID-19 needs to be established in rigorous safety and efficacy studies. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1208/s12248-021-00666-x.
【저자키워드】 SARS-CoV-2, Chloroquine, Hydroxychloroquine, aerosol, inhalation, PBPK, 【초록키워드】 COVID-19, Efficacy, coronavirus, Chloroquine, Hydroxychloroquine, lung, Toxicity, pharmacokinetics, Local, drug, in vitro, severe acute respiratory syndrome Coronavirus, Aerosols, viability, humans, inhalation, Clinical significance, Inhaled, epithelial cells, respiratory tract, respiratory, cell viability, pharmacokinetic, administration, Concentration, dose, exposure to, oral administration, target tissue, acute respiratory syndrome, Abstract, electrical resistance, supplementary material, acute respiratory syndrome coronavirus, tissue, acute respiratory syndrome coronavirus 2, treat, these compounds, primary human bronchial epithelial cells, transepithelial electrical resistance, thermal, pharmacological, effective, Cell, concentrations, significant changes in, predicted, evaluated, characterized, these compound, bronchial epithelial cell, lysosomal, physicochemical property, 【제목키워드】 Chloroquine, Hydroxychloroquine, Human, prediction, pulmonary, delivery, Dosing,