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

Aditya R Kolli,Florian Calvino-Martin,Julia Hoeng

doi:10.1007/s11095-021-03152-3

Aditya R Kolli, Florian Calvino-Martin + Show 1 more

Open Access

https://doi.org/10.1007/s11095-021-03152-3

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Abstract

PurposeChloroquine 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.MethodsWe 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.ResultsAt 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.ConclusionOur 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

Highlights

Respiratory viruses are transmitted from person to person and cause diseases in humans, some of which have high morbidity and mortality
We have recently developed a physiologically based pharmacokinetic (PBPK) model for CQ and HCQ, which consists of 16 tissue compartments [38]
The permeabilities of the unionized species were estimated by using initial values from Trapp et al to fit the experimental data, and those of the protonated species were set at 6.5 log units lower (6.5 for +1 and 13 for +2 charge) than the permeabilities of the unionized species [39]

Summary

Introduction

Respiratory viruses are transmitted from person to person and cause diseases in humans, some of which have high morbidity and mortality. The binding of viruses to cellular surface receptors and entry into epithelial cells is efficient under acidic environments [8]; the viruses may undergo endocytosis or nonendocytic fusion to enter cells. Earlier studies have shown that adenoviruses [10], coronaviruses [11], and influenza viruses [12] require acidified endolysosomes for viral infection. Compounds such as bafilomycin A1, ammonium chloride, chloroquine (CQ), and hydroxychloroquine (HCQ) have been shown to lower endolysosomal acidification and inhibit viral replication in vitro [13,14,15,16]

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