{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T23:56:08Z","timestamp":1768262168097,"version":"3.49.0"},"reference-count":50,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T00:00:00Z","timestamp":1721174400000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The urgent need for safe, efficacious, and accessible drug treatments to treat coronavirus disease 2019 (COVID\u201019) prompted a global effort to evaluate drug repurposing opportunities. Pyronaridine and amodiaquine are both components of approved antimalarials with in\u00a0vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS\u2010CoV\u20102). In\u00a0vitro activity does not always translate to clinical efficacy across a therapeutic dose range. This study applied available, verified, physiologically based pharmacokinetic (PBPK) models for pyronaridine, amodiaquine, and its active metabolite N\u2010desethylamodiaquine (DEAQ) to predict drug concentrations in lung tissue relative to plasma or blood in the default healthy virtual population. Lung exposures were compared to published data across the reported range of in\u00a0vitro EC<jats:sub>50<\/jats:sub> values against SARS\u2010CoV\u20102. In the multicompartment permeability\u2010limited PBPK model, the predicted total <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> in lung mass for pyronaridine was 34.2\u2009\u03bcM on Day 3, 30.5\u2010fold greater than in blood (1.12\u2009\u03bcM) and for amodiaquine was 0.530\u2009\u03bcM, 8.83\u2010fold greater than in plasma (0.060\u2009\u03bcM). In the perfusion\u2010limited PBPK model, the DEAQ predicted total <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> on Day 3 in lung mass (30.2\u2009\u03bcM) was 21.4\u2010fold greater than for plasma (1.41\u2009\u03bcM). Based on the available in\u00a0vitro data, predicted drug concentrations in lung tissue for pyronaridine and DEAQ, but not amodiaquine, appeared sufficient to inhibit SARS\u2010CoV\u20102 replication. Simulations indicated standard dosing regimens of pyronaridine\u2010artesunate and artesunate\u2010amodiaquine have potential to treat COVID\u201019. These findings informed repurposing strategies to select the most relevant compounds for clinical investigation in COVID\u201019. Clinical data for model verification may become available from ongoing clinical studies.<\/jats:p>","DOI":"10.1111\/cts.13865","type":"journal-article","created":{"date-parts":[[2024,7,18]],"date-time":"2024-07-18T04:40:49Z","timestamp":1721277649000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["PBPK\u2010led assessment of antimalarial drugs as candidates for Covid\u201019: Simulating concentrations at the site of action to inform repurposing strategies"],"prefix":"10.1111","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5912-744X","authenticated-orcid":false,"given":"Nada","family":"Abla","sequence":"first","affiliation":[{"name":"MMV Medicines for Malaria Venture  Geneva Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6684-4287","authenticated-orcid":false,"given":"Lisa M.","family":"Almond","sequence":"additional","affiliation":[{"name":"Certara UK Ltd  Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7111-7837","authenticated-orcid":false,"given":"Jennifer J.","family":"Bonner","sequence":"additional","affiliation":[{"name":"Certara UK Ltd  Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4817-0482","authenticated-orcid":false,"given":"Naomi","family":"Richardson","sequence":"additional","affiliation":[{"name":"Magenta Communications Ltd  Abingdon UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9796-847X","authenticated-orcid":false,"given":"Timothy N. C.","family":"Wells","sequence":"additional","affiliation":[{"name":"MMV Medicines for Malaria Venture  Geneva Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0769-9649","authenticated-orcid":false,"given":"J\u00f6rg J.","family":"M\u00f6hrle","sequence":"additional","affiliation":[{"name":"MMV Medicines for Malaria Venture  Geneva Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,7,17]]},"reference":[{"key":"e_1_2_11_2_1","volume-title":"A Comprehensive View of Global Deaths Directly and Indirectly Associated with the COVID\u201019 Pandemic","author":"World Health Organization","year":"2022"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygeno.2021.05.006"},{"key":"e_1_2_11_4_1","volume-title":"Therapeutics and COVID\u201019: Living Guideline","author":"World Health Organization","year":"2022"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2020.118205"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01218-20"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00819-20"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsptsci.0c00131"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tmaid.2020.101873"},{"key":"e_1_2_11_10_1","doi-asserted-by":"crossref","unstructured":"BaeJ\u2010Y LeeGE ParkH et\u00a0al.Pyronaridine and artesunate are potential antiviral drugs against COVID\u201019 and influenza.BioRxiv.2020.","DOI":"10.1101\/2020.07.28.225102"},{"key":"e_1_2_11_11_1","volume-title":"Pyramax: Product Information","author":"European Medicines Agency","year":"2022"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.03829-14"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02716-14"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.0c05996"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1080\/14786419.2022.2057492"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.108959"},{"key":"e_1_2_11_17_1","first-page":"1147","article-title":"Pyronaridine protects against SARS\u2010CoV\u20102 infection in mouse. ACS","volume":"8","author":"Puhl AC","year":"2022","journal-title":"Infect Dis"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2021.114016"},{"key":"e_1_2_11_19_1","volume-title":"Artesunate & AMODIAQUINE Tablets: Summary of Product Characteristics","author":"Sanofi","year":"2013"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1987.tb03002.x"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00637573"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkt513"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-021-00718-9"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.26397"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41597-022-01532-x"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2021.105127"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dsx.2020.04.020"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1955"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-022-03373-0"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13013"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12034"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciaa237"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.2217\/fmb-2021-0019"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2024.156503"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10238-021-00686-z"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04479-6"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(20)30434-5"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.meegid.2022.105254"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics15030838"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkab160"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.02916-22"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.814134"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2445"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14668"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.104322"},{"key":"e_1_2_11_46_1","volume-title":"ANTICOV: platform Trial to Find Early Treatment Options for COVID\u201019 in Low\u2010Resource Settings","author":"Drugs for Neglected Diseases Initiative","year":"2022"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1099425"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12249-023-02627-3"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2022.106163"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.12793\/tcp.2022.30.e20"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12975"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.13865","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T18:49:29Z","timestamp":1721933369000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.13865"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7]]},"references-count":50,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2024,7]]}},"alternative-id":["10.1111\/cts.13865"],"URL":"https:\/\/doi.org\/10.1111\/cts.13865","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7]]},"assertion":[{"value":"2023-12-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e13865"}}