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The PBPK LeiCNS-PK3.0 framework predicts Nirmatrelvir (but not Remdesivir or Molnupiravir) to achieve effective concentrations against SARS-CoV-2 in human brain cells

SARS-CoV-2 was shown to infect and persist in the human brain cells for up to 230 days, highlighting the need to treat the brain viral load. The CNS disposition of the antiCOVID-19 drugs: Remdesivir, Molnupiravir, and Nirmatrelvir, remains, however, unexplored. Here, we assessed the human brain phar...

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Autores principales: Saleh, Mohammed A.A., Hirasawa, Makoto, Sun, Ming, Gülave, Berfin, Elassaiss-Schaap, Jeroen, de Lange, Elizabeth C.M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Authors. Published by Elsevier B.V. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9710098/
https://www.ncbi.nlm.nih.gov/pubmed/36462547
http://dx.doi.org/10.1016/j.ejps.2022.106345
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author Saleh, Mohammed A.A.
Hirasawa, Makoto
Sun, Ming
Gülave, Berfin
Elassaiss-Schaap, Jeroen
de Lange, Elizabeth C.M.
author_facet Saleh, Mohammed A.A.
Hirasawa, Makoto
Sun, Ming
Gülave, Berfin
Elassaiss-Schaap, Jeroen
de Lange, Elizabeth C.M.
author_sort Saleh, Mohammed A.A.
collection PubMed
description SARS-CoV-2 was shown to infect and persist in the human brain cells for up to 230 days, highlighting the need to treat the brain viral load. The CNS disposition of the antiCOVID-19 drugs: Remdesivir, Molnupiravir, and Nirmatrelvir, remains, however, unexplored. Here, we assessed the human brain pharmacokinetic profile (PK) against the EC(90) values of the antiCOVID-19 drugs to predict drugs with favorable brain PK against the delta and the omicron variants. We also evaluated the intracellular PK of GS443902 and EIDD2061, the active metabolites of Remdesivir and Molnupiravir, respectively. Towards this, we applied LeiCNS-PK3.0, the physiologically based pharmacokinetic framework with demonstrated adequate predictions of human CNS PK. Under the recommended dosing regimens, the predicted brain extracellular fluid PK of only Nirmatrelvir was above the variants’ EC(90). The intracellular levels of GS443902 and EIDD2061 were below the intracellular EC(90). Summarizing, our model recommends Nirmatrelvir as the promising candidate for (pre)clinical studies investigating the CNS efficacy of antiCOVID-19 drugs.
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spelling pubmed-97100982022-11-30 The PBPK LeiCNS-PK3.0 framework predicts Nirmatrelvir (but not Remdesivir or Molnupiravir) to achieve effective concentrations against SARS-CoV-2 in human brain cells Saleh, Mohammed A.A. Hirasawa, Makoto Sun, Ming Gülave, Berfin Elassaiss-Schaap, Jeroen de Lange, Elizabeth C.M. Eur J Pharm Sci Article SARS-CoV-2 was shown to infect and persist in the human brain cells for up to 230 days, highlighting the need to treat the brain viral load. The CNS disposition of the antiCOVID-19 drugs: Remdesivir, Molnupiravir, and Nirmatrelvir, remains, however, unexplored. Here, we assessed the human brain pharmacokinetic profile (PK) against the EC(90) values of the antiCOVID-19 drugs to predict drugs with favorable brain PK against the delta and the omicron variants. We also evaluated the intracellular PK of GS443902 and EIDD2061, the active metabolites of Remdesivir and Molnupiravir, respectively. Towards this, we applied LeiCNS-PK3.0, the physiologically based pharmacokinetic framework with demonstrated adequate predictions of human CNS PK. Under the recommended dosing regimens, the predicted brain extracellular fluid PK of only Nirmatrelvir was above the variants’ EC(90). The intracellular levels of GS443902 and EIDD2061 were below the intracellular EC(90). Summarizing, our model recommends Nirmatrelvir as the promising candidate for (pre)clinical studies investigating the CNS efficacy of antiCOVID-19 drugs. The Authors. Published by Elsevier B.V. 2023-02-01 2022-11-30 /pmc/articles/PMC9710098/ /pubmed/36462547 http://dx.doi.org/10.1016/j.ejps.2022.106345 Text en © 2022 The Authors. Published by Elsevier B.V. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Article
Saleh, Mohammed A.A.
Hirasawa, Makoto
Sun, Ming
Gülave, Berfin
Elassaiss-Schaap, Jeroen
de Lange, Elizabeth C.M.
The PBPK LeiCNS-PK3.0 framework predicts Nirmatrelvir (but not Remdesivir or Molnupiravir) to achieve effective concentrations against SARS-CoV-2 in human brain cells
title The PBPK LeiCNS-PK3.0 framework predicts Nirmatrelvir (but not Remdesivir or Molnupiravir) to achieve effective concentrations against SARS-CoV-2 in human brain cells
title_full The PBPK LeiCNS-PK3.0 framework predicts Nirmatrelvir (but not Remdesivir or Molnupiravir) to achieve effective concentrations against SARS-CoV-2 in human brain cells
title_fullStr The PBPK LeiCNS-PK3.0 framework predicts Nirmatrelvir (but not Remdesivir or Molnupiravir) to achieve effective concentrations against SARS-CoV-2 in human brain cells
title_full_unstemmed The PBPK LeiCNS-PK3.0 framework predicts Nirmatrelvir (but not Remdesivir or Molnupiravir) to achieve effective concentrations against SARS-CoV-2 in human brain cells
title_short The PBPK LeiCNS-PK3.0 framework predicts Nirmatrelvir (but not Remdesivir or Molnupiravir) to achieve effective concentrations against SARS-CoV-2 in human brain cells
title_sort pbpk leicns-pk3.0 framework predicts nirmatrelvir (but not remdesivir or molnupiravir) to achieve effective concentrations against sars-cov-2 in human brain cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9710098/
https://www.ncbi.nlm.nih.gov/pubmed/36462547
http://dx.doi.org/10.1016/j.ejps.2022.106345
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