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However, they lack antiviral efficacy upon oral administration. Translation of <jats:italic>in vitro<\/jats:italic> to <jats:italic>in vivo<\/jats:italic> exposure is necessary for understanding the disconnect between the two to develop effective therapeutic strategies.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We employed an <jats:italic>in vitro<\/jats:italic> 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>At their reported <jats:italic>in vitro<\/jats:italic> 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 <jats:italic>in vitro<\/jats:italic>. The predicted cellular and lysosomal concentrations in the respiratory tract for <jats:italic>in vivo<\/jats:italic> oral doses are lower than the <jats:italic>in vitro<\/jats:italic> effective levels. Pulmonary administration of aerosolized chloroquine or hydroxychloroquine is predicted to achieve high bound <jats:italic>in vitro<\/jats:italic>-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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Our analysis provides a framework for extrapolating <jats:italic>in vitro<\/jats:italic> effective concentrations of chloroquine and hydroxychloroquine to <jats:italic>in vivo<\/jats:italic> dosing regimens for treating viral respiratory infections.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Graphical abstract<\/jats:title>\n                \n              <\/jats:sec>","DOI":"10.1007\/s11095-021-03152-3","type":"journal-article","created":{"date-parts":[[2022,1,9]],"date-time":"2022-01-09T00:03:33Z","timestamp":1641686613000},"page":"57-73","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Translational Modeling of Chloroquine and Hydroxychloroquine Dosimetry in Human Airways for Treating Viral Respiratory Infections"],"prefix":"10.1007","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4275-4260","authenticated-orcid":false,"given":"Aditya R.","family":"Kolli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Calvino-Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Hoeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,9]]},"reference":[{"key":"3152_CR1","doi-asserted-by":"publisher","unstructured":"Boncristiani HF, Criado MF, Arruda E. 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