Translational Modeling of Chloroquine and Hydroxychloroquine Dosimetry in Human Airways for Treating Viral Respiratory Infections

Abstract

Purpose Chloroquine and hydroxychloroquine are effective against respiratory viruses in vitro. However, they lack antiviral efficacy upon oral administration. Translation of in vitro to in vivo exposure is necessary for understanding the disconnect between the two to develop effective therapeutic strategies. Methods We employed an in vitro ion-trapping kinetic model to predict the changes in the cytosolic and lysosomal concentrations of chloroquine and hydroxychloroquine in cell lines and primary human airway cultures. A physiologically based pharmacokinetic model with detailed respiratory physiology was used to predict regional airway exposure and optimize dosing regimens. Results At their reported in vitro effective concentrations in cell lines, chloroquine and hydroxychloroquine cause a significant increase in their cytosolic and lysosomal concentrations by altering the lysosomal pH. Higher concentrations of the compounds are required to achieve similar levels of cytosolic and lysosomal changes in primary human airway cells in vitro. The predicted cellular and lysosomal concentrations in the respiratory tract for in vivo oral doses are lower than the in vitro effective levels. Pulmonary administration of aerosolized chloroquine or hydroxychloroquine is predicted to achieve high bound in vitro-effective concentrations in the respiratory tract, with low systemic exposure. Achieving effective cytosolic concentrations for activating immunomodulatory effects and adequate lysosomal levels for inhibiting viral replication could be key drivers for treating viral respiratory infections. Conclusion Our analysis provides a framework for extrapolating in vitro effective concentrations of chloroquine and hydroxychloroquine to in vivo dosing regimens for treating viral respiratory infections. Graphical abstract

Physiologically Based Modelling Framework for Prediction of Pulmonary Pharmacokinetics of Antimicrobial Target Site Concentrations

“…However, HCQ was found ineffective as a COVID treatment [ 34 , 35 ]. The lung-plasma partitioning ratio of HCQ is very high, but this high partitioning was a result of lysosomal trapping [ 36 – 38 ]. Moreover, in vitro efficacy had been related to cell culture media concentrations [ 33 ], which corresponds to extracellular fluid.…”

Synthesis and mechanism of biological action of morpholinyl-bearing arylsquaramides as small-molecule lysosomal pH modulators

“…1 These so-called lysosomal pH modulators generally function by acting as a weak base/acid, or releasing a basic/acidic component in lysosomal environments to elevate/lower lysosomal pH. 1 For example, chloroquine and hydroxychloroquine inhibit lysosomal acidification through elevating lysosomal pH, 17–19 whereas poly(lactic-co-glycolic acid) (PLGA) degrades in an acidic environment to release lactic and glycolic component carboxylic acids to lower lysosomal pH (Fig. 1).…”