Pulmonary Delivery of Aerosolized Chloroquine and Hydroxychloroquine to Treat COVID-19: In Vitro Experimentation to Human Dosing Predictions

February 7, 2022

Aditya R. Kolli, 1 Tanja Zivkovic Semren, 1 David Bovard, 1 Shoaib Majeed, 1 Marco van der Toorn, 1 Sophie Scheuner, 1 Philippe A. Guy, 1 Arkadiusz Kuczaj, 1 Anatoly Mazurov, 1 Stefan Frentzel, 1 Florian Calvino-Martin, 1 Nikolai V. Ivanov, 1 John O’Mullane, 1 Manuel C. Peitsch, 1 and Julia Hoeng 1
1 PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000, Neuchâtel, Switzerland

This study shows formulated CQ and HCQ aerosols with respirable particles for use in the treatment of COVID-19. An in vitro assessment in human bronchial epithelial cells showed no adverse effects on cell viability, TEER, or ciliary beating. Modeling CQ and HCQ exposures in vitro in the Vitrocell 24 exposure system and in an IPML model enabled the validation of transport kinetics across the airway epithelial barrier.

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 physico- chemical 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 concen- trations. 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.

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