Prioritization of Anti-SARS-Cov-2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics.
Identifieur interne : 001621 ( Main/Corpus ); précédent : 001620; suivant : 001622Prioritization of Anti-SARS-Cov-2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics.
Auteurs : Usman Arshad ; Henry Pertinez ; Helen Box ; Lee Tatham ; Rajith K R. Rajoli ; Paul Curley ; Megan Neary ; Joanne Sharp ; Neill J. Liptrott ; Anthony Valentijn ; Christopher David ; Steve P. Rannard ; Paul M. O'Neill ; Ghaith Aljayyoussi ; Shaun H. Pennington ; Stephen A. Ward ; Andrew Hill ; David J. Back ; Saye H. Khoo ; Patrick G. Bray ; Giancarlo A. Biagini ; Andrew OwenSource :
- Clinical pharmacology and therapeutics [ 1532-6535 ] ; 2020.
English descriptors
- KwdEn :
- Antiviral Agents (administration & dosage), Antiviral Agents (blood), Betacoronavirus (drug effects), COVID-19 (MeSH), Coronavirus Infections (blood), Coronavirus Infections (drug therapy), Drug Delivery Systems (methods), Drug Repositioning (methods), Humans (MeSH), Pandemics (MeSH), Pneumonia, Viral (blood), Pneumonia, Viral (drug therapy), SARS-CoV-2 (MeSH).
- MESH :
- chemical , administration & dosage : Antiviral Agents.
- chemical , blood : Antiviral Agents.
- blood : Coronavirus Infections, Pneumonia, Viral.
- drug effects : Betacoronavirus.
- drug therapy : Coronavirus Infections, Pneumonia, Viral.
- methods : Drug Delivery Systems, Drug Repositioning.
- COVID-19, Humans, Pandemics, SARS-CoV-2.
Abstract
There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). However, this has not been accompanied by a comprehensive evaluation of the target plasma and lung concentrations of these drugs following approved dosing in humans. Accordingly, concentration 90% (EC90 ) values recalculated from in vitro anti-SARS-CoV-2 activity data was expressed as a ratio to the achievable maximum plasma concentration (Cmax ) at an approved dose in humans (Cmax /EC90 ratio). Only 14 of the 56 analyzed drugs achieved a Cmax /EC90 ratio above 1. A more in-depth assessment demonstrated that only nitazoxanide, nelfinavir, tipranavir (ritonavir-boosted), and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval. An unbound lung to plasma tissue partition coefficient (Kp Ulung ) was also simulated to derive a lung Cmax /half-maximal effective concentration (EC50 ) as a better indicator of potential human efficacy. Hydroxychloroquine, chloroquine, mefloquine, atazanavir (ritonavir-boosted), tipranavir (ritonavir-boosted), ivermectin, azithromycin, and lopinavir (ritonavir-boosted) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50 . Nitazoxanide and sulfadoxine also exceeded their reported EC50 by 7.8-fold and 1.5-fold in lung, respectively. This analysis may be used to select potential candidates for further clinical testing, while deprioritizing compounds unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments, such as the lungs, in order to maximize the potential for success of proposed human clinical trials.
DOI: 10.1002/cpt.1909
PubMed: 32438446
PubMed Central: PMC7280633
Links to Exploration step
pubmed:32438446Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Prioritization of Anti-SARS-Cov-2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics.</title><author><name sortKey="Arshad, Usman" sort="Arshad, Usman" uniqKey="Arshad U" first="Usman" last="Arshad">Usman Arshad</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Pertinez, Henry" sort="Pertinez, Henry" uniqKey="Pertinez H" first="Henry" last="Pertinez">Henry Pertinez</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Box, Helen" sort="Box, Helen" uniqKey="Box H" first="Helen" last="Box">Helen Box</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Tatham, Lee" sort="Tatham, Lee" uniqKey="Tatham L" first="Lee" last="Tatham">Lee Tatham</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Rajoli, Rajith K R" sort="Rajoli, Rajith K R" uniqKey="Rajoli R" first="Rajith K R" last="Rajoli">Rajith K R. Rajoli</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Curley, Paul" sort="Curley, Paul" uniqKey="Curley P" first="Paul" last="Curley">Paul Curley</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Neary, Megan" sort="Neary, Megan" uniqKey="Neary M" first="Megan" last="Neary">Megan Neary</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Sharp, Joanne" sort="Sharp, Joanne" uniqKey="Sharp J" first="Joanne" last="Sharp">Joanne Sharp</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Liptrott, Neill J" sort="Liptrott, Neill J" uniqKey="Liptrott N" first="Neill J" last="Liptrott">Neill J. Liptrott</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Valentijn, Anthony" sort="Valentijn, Anthony" uniqKey="Valentijn A" first="Anthony" last="Valentijn">Anthony Valentijn</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="David, Christopher" sort="David, Christopher" uniqKey="David C" first="Christopher" last="David">Christopher David</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Rannard, Steve P" sort="Rannard, Steve P" uniqKey="Rannard S" first="Steve P" last="Rannard">Steve P. Rannard</name><affiliation><nlm:affiliation>Department of Chemistry, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="O Neill, Paul M" sort="O Neill, Paul M" uniqKey="O Neill P" first="Paul M" last="O'Neill">Paul M. O'Neill</name><affiliation><nlm:affiliation>Department of Chemistry, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Aljayyoussi, Ghaith" sort="Aljayyoussi, Ghaith" uniqKey="Aljayyoussi G" first="Ghaith" last="Aljayyoussi">Ghaith Aljayyoussi</name><affiliation><nlm:affiliation>Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Centre for Drugs and Diagnostics, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Pennington, Shaun H" sort="Pennington, Shaun H" uniqKey="Pennington S" first="Shaun H" last="Pennington">Shaun H. Pennington</name><affiliation><nlm:affiliation>Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Centre for Drugs and Diagnostics, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Ward, Stephen A" sort="Ward, Stephen A" uniqKey="Ward S" first="Stephen A" last="Ward">Stephen A. Ward</name><affiliation><nlm:affiliation>Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Centre for Drugs and Diagnostics, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Hill, Andrew" sort="Hill, Andrew" uniqKey="Hill A" first="Andrew" last="Hill">Andrew Hill</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Back, David J" sort="Back, David J" uniqKey="Back D" first="David J" last="Back">David J. Back</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Khoo, Saye H" sort="Khoo, Saye H" uniqKey="Khoo S" first="Saye H" last="Khoo">Saye H. Khoo</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Bray, Patrick G" sort="Bray, Patrick G" uniqKey="Bray P" first="Patrick G" last="Bray">Patrick G. Bray</name><affiliation><nlm:affiliation>Pat Bray Electrical, Wigan, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Biagini, Giancarlo A" sort="Biagini, Giancarlo A" uniqKey="Biagini G" first="Giancarlo A" last="Biagini">Giancarlo A. Biagini</name><affiliation><nlm:affiliation>Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Centre for Drugs and Diagnostics, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Owen, Andrew" sort="Owen, Andrew" uniqKey="Owen A" first="Andrew" last="Owen">Andrew Owen</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:32438446</idno><idno type="pmid">32438446</idno><idno type="doi">10.1002/cpt.1909</idno><idno type="pmc">PMC7280633</idno><idno type="wicri:Area/Main/Corpus">001621</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">001621</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Prioritization of Anti-SARS-Cov-2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics.</title><author><name sortKey="Arshad, Usman" sort="Arshad, Usman" uniqKey="Arshad U" first="Usman" last="Arshad">Usman Arshad</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Pertinez, Henry" sort="Pertinez, Henry" uniqKey="Pertinez H" first="Henry" last="Pertinez">Henry Pertinez</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Box, Helen" sort="Box, Helen" uniqKey="Box H" first="Helen" last="Box">Helen Box</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Tatham, Lee" sort="Tatham, Lee" uniqKey="Tatham L" first="Lee" last="Tatham">Lee Tatham</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Rajoli, Rajith K R" sort="Rajoli, Rajith K R" uniqKey="Rajoli R" first="Rajith K R" last="Rajoli">Rajith K R. Rajoli</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Curley, Paul" sort="Curley, Paul" uniqKey="Curley P" first="Paul" last="Curley">Paul Curley</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Neary, Megan" sort="Neary, Megan" uniqKey="Neary M" first="Megan" last="Neary">Megan Neary</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Sharp, Joanne" sort="Sharp, Joanne" uniqKey="Sharp J" first="Joanne" last="Sharp">Joanne Sharp</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Liptrott, Neill J" sort="Liptrott, Neill J" uniqKey="Liptrott N" first="Neill J" last="Liptrott">Neill J. Liptrott</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Valentijn, Anthony" sort="Valentijn, Anthony" uniqKey="Valentijn A" first="Anthony" last="Valentijn">Anthony Valentijn</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="David, Christopher" sort="David, Christopher" uniqKey="David C" first="Christopher" last="David">Christopher David</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Rannard, Steve P" sort="Rannard, Steve P" uniqKey="Rannard S" first="Steve P" last="Rannard">Steve P. Rannard</name><affiliation><nlm:affiliation>Department of Chemistry, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="O Neill, Paul M" sort="O Neill, Paul M" uniqKey="O Neill P" first="Paul M" last="O'Neill">Paul M. O'Neill</name><affiliation><nlm:affiliation>Department of Chemistry, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Aljayyoussi, Ghaith" sort="Aljayyoussi, Ghaith" uniqKey="Aljayyoussi G" first="Ghaith" last="Aljayyoussi">Ghaith Aljayyoussi</name><affiliation><nlm:affiliation>Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Centre for Drugs and Diagnostics, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Pennington, Shaun H" sort="Pennington, Shaun H" uniqKey="Pennington S" first="Shaun H" last="Pennington">Shaun H. Pennington</name><affiliation><nlm:affiliation>Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Centre for Drugs and Diagnostics, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Ward, Stephen A" sort="Ward, Stephen A" uniqKey="Ward S" first="Stephen A" last="Ward">Stephen A. Ward</name><affiliation><nlm:affiliation>Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Centre for Drugs and Diagnostics, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Hill, Andrew" sort="Hill, Andrew" uniqKey="Hill A" first="Andrew" last="Hill">Andrew Hill</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Back, David J" sort="Back, David J" uniqKey="Back D" first="David J" last="Back">David J. Back</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Khoo, Saye H" sort="Khoo, Saye H" uniqKey="Khoo S" first="Saye H" last="Khoo">Saye H. Khoo</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Bray, Patrick G" sort="Bray, Patrick G" uniqKey="Bray P" first="Patrick G" last="Bray">Patrick G. Bray</name><affiliation><nlm:affiliation>Pat Bray Electrical, Wigan, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Biagini, Giancarlo A" sort="Biagini, Giancarlo A" uniqKey="Biagini G" first="Giancarlo A" last="Biagini">Giancarlo A. Biagini</name><affiliation><nlm:affiliation>Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Centre for Drugs and Diagnostics, Liverpool, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Owen, Andrew" sort="Owen, Andrew" uniqKey="Owen A" first="Andrew" last="Owen">Andrew Owen</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Clinical pharmacology and therapeutics</title><idno type="eISSN">1532-6535</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral Agents (administration & dosage)</term><term>Antiviral Agents (blood)</term><term>Betacoronavirus (drug effects)</term><term>COVID-19 (MeSH)</term><term>Coronavirus Infections (blood)</term><term>Coronavirus Infections (drug therapy)</term><term>Drug Delivery Systems (methods)</term><term>Drug Repositioning (methods)</term><term>Humans (MeSH)</term><term>Pandemics (MeSH)</term><term>Pneumonia, Viral (blood)</term><term>Pneumonia, Viral (drug therapy)</term><term>SARS-CoV-2 (MeSH)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="administration & dosage" xml:lang="en"><term>Antiviral Agents</term></keywords><keywords scheme="MESH" type="chemical" qualifier="blood" xml:lang="en"><term>Antiviral Agents</term></keywords><keywords scheme="MESH" qualifier="blood" xml:lang="en"><term>Coronavirus Infections</term><term>Pneumonia, Viral</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Betacoronavirus</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Coronavirus Infections</term><term>Pneumonia, Viral</term></keywords><keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Drug Delivery Systems</term><term>Drug Repositioning</term></keywords><keywords scheme="MESH" xml:lang="en"><term>COVID-19</term><term>Humans</term><term>Pandemics</term><term>SARS-CoV-2</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). However, this has not been accompanied by a comprehensive evaluation of the target plasma and lung concentrations of these drugs following approved dosing in humans. Accordingly, concentration 90% (EC<sub>90</sub> ) values recalculated from in vitro anti-SARS-CoV-2 activity data was expressed as a ratio to the achievable maximum plasma concentration (C<sub>max</sub> ) at an approved dose in humans (C<sub>max</sub> /EC<sub>90</sub> ratio). Only 14 of the 56 analyzed drugs achieved a C<sub>max</sub> /EC<sub>90</sub> ratio above 1. A more in-depth assessment demonstrated that only nitazoxanide, nelfinavir, tipranavir (ritonavir-boosted), and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval. An unbound lung to plasma tissue partition coefficient (K<sub>p</sub> U<sub>lung</sub> ) was also simulated to derive a lung C<sub>max</sub> /half-maximal effective concentration (EC<sub>50</sub> ) as a better indicator of potential human efficacy. Hydroxychloroquine, chloroquine, mefloquine, atazanavir (ritonavir-boosted), tipranavir (ritonavir-boosted), ivermectin, azithromycin, and lopinavir (ritonavir-boosted) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC<sub>50</sub> . Nitazoxanide and sulfadoxine also exceeded their reported EC<sub>50</sub> by 7.8-fold and 1.5-fold in lung, respectively. This analysis may be used to select potential candidates for further clinical testing, while deprioritizing compounds unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC<sub>90</sub> values and discuss findings in the context of achievable exposures in humans, especially within target compartments, such as the lungs, in order to maximize the potential for success of proposed human clinical trials.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">32438446</PMID><DateCompleted><Year>2020</Year><Month>09</Month><Day>29</Day></DateCompleted><DateRevised><Year>2021</Year><Month>04</Month><Day>19</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1532-6535</ISSN><JournalIssue CitedMedium="Internet"><Volume>108</Volume><Issue>4</Issue><PubDate><Year>2020</Year><Month>10</Month></PubDate></JournalIssue><Title>Clinical pharmacology and therapeutics</Title><ISOAbbreviation>Clin Pharmacol Ther</ISOAbbreviation></Journal><ArticleTitle>Prioritization of Anti-SARS-Cov-2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics.</ArticleTitle><Pagination><MedlinePgn>775-790</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1002/cpt.1909</ELocationID><Abstract><AbstractText>There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). However, this has not been accompanied by a comprehensive evaluation of the target plasma and lung concentrations of these drugs following approved dosing in humans. Accordingly, concentration 90% (EC<sub>90</sub> ) values recalculated from in vitro anti-SARS-CoV-2 activity data was expressed as a ratio to the achievable maximum plasma concentration (C<sub>max</sub> ) at an approved dose in humans (C<sub>max</sub> /EC<sub>90</sub> ratio). Only 14 of the 56 analyzed drugs achieved a C<sub>max</sub> /EC<sub>90</sub> ratio above 1. A more in-depth assessment demonstrated that only nitazoxanide, nelfinavir, tipranavir (ritonavir-boosted), and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval. An unbound lung to plasma tissue partition coefficient (K<sub>p</sub> U<sub>lung</sub> ) was also simulated to derive a lung C<sub>max</sub> /half-maximal effective concentration (EC<sub>50</sub> ) as a better indicator of potential human efficacy. Hydroxychloroquine, chloroquine, mefloquine, atazanavir (ritonavir-boosted), tipranavir (ritonavir-boosted), ivermectin, azithromycin, and lopinavir (ritonavir-boosted) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC<sub>50</sub> . Nitazoxanide and sulfadoxine also exceeded their reported EC<sub>50</sub> by 7.8-fold and 1.5-fold in lung, respectively. This analysis may be used to select potential candidates for further clinical testing, while deprioritizing compounds unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC<sub>90</sub> values and discuss findings in the context of achievable exposures in humans, especially within target compartments, such as the lungs, in order to maximize the potential for success of proposed human clinical trials.</AbstractText><CopyrightInformation>© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Arshad</LastName><ForeName>Usman</ForeName><Initials>U</Initials><Identifier Source="ORCID">0000-0003-1586-1885</Identifier><AffiliationInfo><Affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pertinez</LastName><ForeName>Henry</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Box</LastName><ForeName>Helen</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tatham</LastName><ForeName>Lee</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rajoli</LastName><ForeName>Rajith K R</ForeName><Initials>RKR</Initials><AffiliationInfo><Affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Curley</LastName><ForeName>Paul</ForeName><Initials>P</Initials><Identifier Source="ORCID">0000-0003-4596-2708</Identifier><AffiliationInfo><Affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Neary</LastName><ForeName>Megan</ForeName><Initials>M</Initials><Identifier Source="ORCID">0000-0002-4960-2139</Identifier><AffiliationInfo><Affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sharp</LastName><ForeName>Joanne</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liptrott</LastName><ForeName>Neill J</ForeName><Initials>NJ</Initials><Identifier Source="ORCID">0000-0002-5980-8966</Identifier><AffiliationInfo><Affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Valentijn</LastName><ForeName>Anthony</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>David</LastName><ForeName>Christopher</ForeName><Initials>C</Initials><Identifier Source="ORCID">0000-0001-8504-2354</Identifier><AffiliationInfo><Affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rannard</LastName><ForeName>Steve P</ForeName><Initials>SP</Initials><Identifier Source="ORCID">0000-0002-6946-1097</Identifier><AffiliationInfo><Affiliation>Department of Chemistry, University of Liverpool, Liverpool, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>O'Neill</LastName><ForeName>Paul M</ForeName><Initials>PM</Initials><AffiliationInfo><Affiliation>Department of Chemistry, University of Liverpool, Liverpool, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Aljayyoussi</LastName><ForeName>Ghaith</ForeName><Initials>G</Initials><Identifier Source="ORCID">0000-0002-5288-4501</Identifier><AffiliationInfo><Affiliation>Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Centre for Drugs and Diagnostics, Liverpool, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pennington</LastName><ForeName>Shaun H</ForeName><Initials>SH</Initials><Identifier Source="ORCID">0000-0002-7160-6275</Identifier><AffiliationInfo><Affiliation>Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Centre for Drugs and Diagnostics, Liverpool, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ward</LastName><ForeName>Stephen A</ForeName><Initials>SA</Initials><Identifier Source="ORCID">0000-0003-2331-3192</Identifier><AffiliationInfo><Affiliation>Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Centre for Drugs and Diagnostics, Liverpool, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hill</LastName><ForeName>Andrew</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Back</LastName><ForeName>David J</ForeName><Initials>DJ</Initials><AffiliationInfo><Affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Khoo</LastName><ForeName>Saye H</ForeName><Initials>SH</Initials><AffiliationInfo><Affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bray</LastName><ForeName>Patrick G</ForeName><Initials>PG</Initials><AffiliationInfo><Affiliation>Pat Bray Electrical, Wigan, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Biagini</LastName><ForeName>Giancarlo A</ForeName><Initials>GA</Initials><Identifier Source="ORCID">0000-0001-6356-6595</Identifier><AffiliationInfo><Affiliation>Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Centre for Drugs and Diagnostics, Liverpool, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Owen</LastName><ForeName>Andrew</ForeName><Initials>A</Initials><Identifier Source="ORCID">0000-0002-9819-7651</Identifier><AffiliationInfo><Affiliation>Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>R01 AI134091</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R24 AI118397</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><Acronym>MRC_</Acronym><Agency>Medical Research Council</Agency><Country>United Kingdom</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>06</Month><Day>14</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Clin Pharmacol Ther</MedlineTA><NlmUniqueID>0372741</NlmUniqueID><ISSNLinking>0009-9236</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000998">Antiviral Agents</NameOfSubstance></Chemical></ChemicalList><CitationSubset>AIM</CitationSubset><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="ErratumIn"><RefSource>Clin Pharmacol Ther. 2021 May;109(5):1362</RefSource><PMID Version="1">33870492</PMID></CommentsCorrections></CommentsCorrectionsList><MeshHeadingList><MeshHeading><DescriptorName UI="D000998" MajorTopicYN="N">Antiviral Agents</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="Y">administration & dosage</QualifierName><QualifierName UI="Q000097" MajorTopicYN="N">blood</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000073640" MajorTopicYN="N">Betacoronavirus</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000086382" MajorTopicYN="N">COVID-19</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018352" MajorTopicYN="N">Coronavirus Infections</DescriptorName><QualifierName UI="Q000097" MajorTopicYN="N">blood</QualifierName><QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016503" MajorTopicYN="N">Drug Delivery Systems</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="Y">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D058492" MajorTopicYN="N">Drug Repositioning</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="Y">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D058873" MajorTopicYN="N">Pandemics</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011024" MajorTopicYN="N">Pneumonia, Viral</DescriptorName><QualifierName UI="Q000097" MajorTopicYN="N">blood</QualifierName><QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000086402" MajorTopicYN="N">SARS-CoV-2</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2020</Year><Month>04</Month><Day>24</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2020</Year><Month>05</Month><Day>18</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>5</Month><Day>22</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>9</Month><Day>30</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2020</Year><Month>5</Month><Day>22</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">32438446</ArticleId><ArticleId IdType="doi">10.1002/cpt.1909</ArticleId><ArticleId IdType="pmc">PMC7280633</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>Gu, J., Han, B. & Wang, J. COVID-19: Gastrointestinal manifestations and potential fecal-oral transmission. Gastroenterology 158, 1518-1519 (2020).</Citation></Reference><Reference><Citation>World Health Organisation. COVID-19 Trials - International Clinical Trials Registry Platform (ICTRP) </Reference><Reference><Citation>Qin, C. et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciaa248.</Citation></Reference><Reference><Citation>Li, W. et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 426, 450-454 (2003).</Citation></Reference><Reference><Citation>Zhao, Y., Zhao, Z., Wang, Y., Zhou, Y., Ma, Y. & Zuo, W. Single-cell RNA expression profiling of ACE2, the receptor of SARS-CoV-2. J bioRxiv. https://doi.org/10.1101/2020.01.26.919985.</Citation></Reference><Reference><Citation>Wu, Y. et al. Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. Lancet Gastroenterol. Hepatol. https://doi.org/10.1016/S2468-1253(20)30083-2.</Citation></Reference><Reference><Citation>Diao, B.H. et al. Kidney is a target for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Infection. J medRxiv. https://doi.org/10.1101/2020.03.04.20031120</Citation></Reference><Reference><Citation>Zhang, C., Shi, L. & Wang, F.S. Liver injury in COVID-19: management and challenges. Lancet Gastroenterol. Hepatol. 5, 428-430 (2020).</Citation></Reference><Reference><Citation>Guo, Y.R. et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status. Mil Med Res 7, 11 (2020).</Citation></Reference><Reference><Citation>Hoffmann, M. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271-280.e8 (2020).</Citation></Reference><Reference><Citation>Zhang, H. et al. The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes. J bioRxiv. https://doi.org/10.1101/2020.01.30.927806.</Citation></Reference><Reference><Citation>Wong, S.H., Lui, R.N. & Sung, J.J. COVID-19 and the digestive system. J. Gastroenterol. Hepatol. 35, 744-748 (2020).</Citation></Reference><Reference><Citation>Zhang, W. et al. Molecular and serological investigation of 2019-nCoV infected patients: implication of multiple shedding routes. Emerg. Microbes Infect. 9, 386-389 (2020).</Citation></Reference><Reference><Citation>Sun, C.B., Wang, Y.-Y., Liu, G.-H., Liu, Z. Role of the Eye in Transmitting Human Coronavirus: What We Know and What We Do Not Know. Frontiers in Public Health 8, (2020). http://dx.doi.org/10.3389/fpubh.2020.00155</Citation></Reference><Reference><Citation>Lu, C.W., Liu, X.F. & Jia, Z.F. 2019-nCoV transmission through the ocular surface must not be ignored. Lancet 395, e39 (2020).</Citation></Reference><Reference><Citation>Smith, C.A., Kulkarni, U., Chen, J. & Goldstein, D.R. Influenza virus inoculum volume is critical to elucidate age-dependent mortality in mice. Aging Cell 18, e12893 (2019).</Citation></Reference><Reference><Citation>Miller, D.S., Kok, T. & Li, P. The virus inoculum volume influences outcome of influenza A infection in mice. Lab. Anim. 47, 74-77 (2013).</Citation></Reference><Reference><Citation>Chen, X. et al. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients. Clin. Infect. Dis.https://doi.org/10.1101/2020.02.29.20029520.</Citation></Reference><Reference><Citation>Liu, Y. et al. Viral dynamics in mild and severe cases of COVID-19. Lancet Infect. Dis. https://doi.org/10.1016/S473-3099(20)30232-2.</Citation></Reference><Reference><Citation>Rodgers, T., Leahy, D. & Rowland, M. Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate-to-strong bases. J. Pharm. Sci. 94, 1259-1276 (2005).</Citation></Reference><Reference><Citation>Rodgers, T. & Rowland, M. Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J. Pharm. Sci. 95, 1238-1257 (2006).</Citation></Reference><Reference><Citation>Rodgers, T. & Rowland, M. Mechanistic approaches to volume of distribution predictions: understanding the processes. Pharm. Res, 24, 918-933 (2007).</Citation></Reference><Reference><Citation>Damle, B., Stogniew, M. & Dowell, J. Pharmacokinetics and tissue distribution of anidulafungin in rats. Antimicrob. Agents Chemother. 52, 2673-2676 (2008).</Citation></Reference><Reference><Citation>Chandrasekaran, A., Ahmad, S., Shen, L., DeMaio, W., Hultin, T. & Scatina, J. Disposition of bazedoxifene in rats. Xenobiotica 40, 578-585 (2010).</Citation></Reference><Reference><Citation>Browning, D.J. Pharmacology of chloroquine and hydroxychloroquine. In: Hydroxychloroquine Chloroquine Retinopathy. 35-63 (Springer, New York, NY, 2014).</Citation></Reference><Reference><Citation>McChesney, E.W., Banks, W.F. Jr & Fabian, R.J. Tissue distribution of chloroquine, hydroxychloroquine, and desethylchloroquine in the rat. Toxicol. Appl. Pharmacol. 10, 501-513 (1967).</Citation></Reference><Reference><Citation>Gupta, A., Tulsankar, S.L., Bhatta, R.S. & Misra, A. Pharmacokinetics, metabolism, and partial biodistribution of "pincer therapeutic" nitazoxanide in mice following pulmonary delivery of inhalable particles. Mol. Pharm. 14, 1204-1211 (2017).</Citation></Reference><Reference><Citation>Lien, E.A., Solheim, E. & Ueland, P.M. Distribution of tamoxifen and its metabolites in rat and human tissues during steady-state treatment. Cancer Res. 51, 4837-4844 (1991).</Citation></Reference><Reference><Citation>Rivulgo, V. et al. Comparative plasma exposure and lung distribution of two human use commercial azithromycin formulations assessed in murine model: a preclinical study. Biomed. Res. Int. 2013, 392010 (2013).</Citation></Reference><Reference><Citation>Moss, L., Wagner, D., Kanaoka, E., Olson, K., Yueh, Y.L. & Bowers, G.D. The comparative disposition and metabolism of dolutegravir, a potent HIV-1 integrase inhibitor, in mice, rats, and monkeys. Xenobiotica 45, 60-70 (2015).</Citation></Reference><Reference><Citation>Kawai, R., Mathew, D., Tanaka, C. & Rowland, M. Physiologically based pharmacokinetics of cyclosporine A: extension to tissue distribution kinetics in rats and scale-up to human. J. Pharmacol. Exp. Ther. 287, 457-468 (1998).</Citation></Reference><Reference><Citation>Pharmaceuticals and Medical Devices Agency (PMDA). Report on the deliberation results - Xospata tablets 40 mg (2018). Accessed May 4, 2020.</Citation> </Reference><Reference><Citation>Bland, J.M. & Altman, D.G. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1, 307-310 (1986).</Citation></Reference><Reference><Citation>Weston, S., Haupt, R., Logue, J., Matthews, K. & Frieman, M.B. FDA approved drugs with broad anti-coronaviral activity inhibit SARS-CoV-2 in vitro. J bioRxiv. https://doi.org/10.1101/2020.03.25.008482.</Citation></Reference><Reference><Citation>Ge, Y. et al. A data-driven drug repositioning framework discovered a potential therapeutic agent targeting COVID-19. J bioRxiv. https://doi.org/10.1101/2020.03.11.986836.</Citation></Reference><Reference><Citation>Bojkova, D. et al. SARS-CoV-2 and SARS-CoV differ in their cell tropism and drug sensitivity profiles. J bioRxiv . https://doi.org/10.1101/2020.04.03.024257.</Citation></Reference><Reference><Citation>Touret, F. et al. In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication. J bioRxiv. https://doi.org/10.1101/2020.04.03.023846.</Citation></Reference><Reference><Citation>Wang, M. et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 30, 269-271 (2020).</Citation></Reference><Reference><Citation>Jeon, S. et al. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs. J bioRxiv. https://doi.org/10.1101/2020.03.20.999730.</Citation></Reference><Reference><Citation>Xu, T., Gao, X., Wu, Z., Selinger, D.W. & Zhou, Z. Indomethacin has a potent antiviral activity against SARS CoV-2 in vitro and canine coronavirus in vivo. J bioRxiv. https://doi.org/10.1101/2020.04.01.017624.</Citation></Reference><Reference><Citation>Fintelman-Rodrigues, N. et al. Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production. J bioRxiv. https://doi.org/10.1101/2020.04.04.020925.</Citation></Reference><Reference><Citation>Yamamoto, N., Matsuyama, S., Hoshino, T. & Yamamoto, N. Nelfinavir inhibits replication of severe acute respiratory syndrome coronavirus 2 in vitro. J bioRxiv. https://doi.org/10.1101/2020.04.06.026476.</Citation></Reference><Reference><Citation>Bukreyeva, N., Mantlo, E.K., Sattler, R.A., Huang, C., Paessler, S. & Zeldis, J. The IMPDH inhibitor merimepodib suppresses SARS-CoV-2 replication in vitro. J bioRxiv. https://doi.org/10.1101/2020.04.07.028589.</Citation></Reference><Reference><Citation>Jin, Z. et al. Structure of Mpro from COVID-19 virus and discovery of its inhibitors. Nature. https://doi.org/10.1038/s41586-020-2223-y.</Citation></Reference><Reference><Citation>Yao, X. et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin. Infect. Dis. https://doi.org/10.1093/cid/ciaa237.</Citation></Reference><Reference><Citation>Choy, K.-T. et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral. Res. 178, 104786 (2020).</Citation></Reference><Reference><Citation>Caly, L., Druce, J.D., Catton, M.G., Jans, D.A. & Wagstaff, K.M. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 178, 104787 (2020).</Citation></Reference><Reference><Citation>Xu, Z. et al. Nelfinavir is active against SARS-CoV-2 in Vero E6. Cells. 10.26434/chemrxiv.12039888.</Citation></Reference><Reference><Citation>Chen, C. et al. Favipiravir versus Arbidol for COVID-19: a randomized clinical trial. J. medRxiv. https://doi.org/10.1101/2020.03.17.20037432.</Citation></Reference><Reference><Citation>Grein, J. et al. Compassionate use of remdesivir for patients with severe Covid-19. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2007016.</Citation></Reference><Reference><Citation>Rossignol, J.F. Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus. J. Infect. Public Health 9, 227-230 (2016).</Citation></Reference><Reference><Citation>Tilmanis, D., van Baalen, C., Oh, D.Y., Rossignol, J.F. & Hurt, A.C. The susceptibility of circulating human influenza viruses to tizoxanide, the active metabolite of nitazoxanide. Antiviral Res. 147, 142-148 (2017).</Citation></Reference><Reference><Citation>Haffizulla, J. et al. Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial. Lancet Infect Dis. 14, 609-618 (2014).</Citation></Reference><Reference><Citation>Gekonge, B., Bardin, M.C. & Montaner, L.J. Short communication: Nitazoxanide inhibits HIV viral replication in monocyte-derived macrophages. AIDS Res. Hum. Retroviruses 31, 237-241 (2015).</Citation></Reference><Reference><Citation>Trabattoni, D. et al. Thiazolides elicit anti-viral innate immunity and reduce HIV replication. Sci. Rep. 6, 27148 (2016).</Citation></Reference><Reference><Citation>Rossignol, J.F. Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antiviral Res. 110, 94-103 (2014).</Citation></Reference><Reference><Citation>Rossignol, J.F., La Frazia, S., Chiappa, L., Ciucci, A. & Santoro, M.G. Thiazolides, a new class of anti-influenza molecules targeting viral hemagglutinin at the post-translational level. J. Biol. Chem. 284, 29798-29808 (2009).</Citation></Reference><Reference><Citation>Hickson, S.E., Margineantu, D., Hockenbery, D.M., Simon, J.A. & Geballe, A.P. Inhibition of vaccinia virus replication by nitazoxanide. Virology 518, 398-405 (2018).</Citation></Reference><Reference><Citation>Wang, Y.M. et al. Antiviral activities of niclosamide and nitazoxanide against chikungunya virus entry and transmission. Antiviral Res. 135, 81-90 (2016).</Citation></Reference><Reference><Citation>Zhang, Y. et al. Site-specific N-glycosylation characterization of recombinant SARS-CoV-2 spike proteins using high-resolution mass spectrometry. J bioRxiv. https://doi.org/10.1101/2020.03.28.013276.</Citation></Reference><Reference><Citation>Clerici, M., Trabattoni, D., Pacei, M., Biasin, M. & Rossignol, J.-F.The anti-infective nitazoxanide shows strong immumodulating effects. J. Immuno. 186, 155.21 (2011).</Citation></Reference><Reference><Citation>Jurgeit, A., McDowell, R., Moese, S., Meldrum, E., Schwendener, R. & Greber, U.F. Niclosamide is a proton carrier and targets acidic endosomes with broad antiviral effects. PLoS Pathog. 8, e1002976 (2012).</Citation></Reference><Reference><Citation>Zhang, X.W. & Yap, Y.L. Old drugs as lead compounds for a new disease? Binding analysis of SARS coronavirus main proteinase with HIV, psychotic and parasite drugs. Bioorg. Med. Chem. 12, 2517-2521 (2004).</Citation></Reference><Reference><Citation>Gassen, N.C. et al. SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection. Nat. Commun. 10, 5770 (2019).</Citation></Reference><Reference><Citation>Li, R. et al. Inhibition of STAT3 by niclosamide synergizes with erlotinib against head and neck cancer. PLoS One 8, e74670 (2013).</Citation></Reference><Reference><Citation>Lin, C.K. et al. Preclinical evaluation of a nanoformulated antihelminthic, niclosamide, in ovarian cancer. Oncotarget 7, 8993-9006 (2016).</Citation></Reference><Reference><Citation>Miner, K. et al. Drug repurposing: the anthelmintics niclosamide and nitazoxanide are potent TMEM16A antagonists that fully bronchodilate airways. Front. Pharmacol. 10, 51 (2019).</Citation></Reference><Reference><Citation>Lv, Z., Chu, Y. & Wang, Y. HIV protease inhibitors: a review of molecular selectivity and toxicity. HIV AIDS (Auckl) 7, 95-104 (2015).</Citation></Reference><Reference><Citation>Streeck, H. & Rockstroh, J.K. Review of tipranavir in the treatment of drug-resistant HIV. Ther. Clin. Risk Manag. 3, 641-651 (2007).</Citation></Reference><Reference><Citation>Sanders, J.M., Monogue, M.L., Jodlowski, T.Z., Cutrell, J.B. pharmacologic treatments for coronavirus disease 2019 (COVID-19). JAMA. https://doi.org/10.1001/jama.2020.6019.</Citation></Reference><Reference><Citation>Justice, A.C. et al. Drug toxicity, HIV progression, or comorbidity of aging: does tipranavir use increase the risk of intracranial hemorrhage? Clin. Infect. Dis. 47, 1226-1230 (2008).</Citation></Reference><Reference><Citation>Flexner, C., Bate, G. & Kirkpatrick, P. Tipranavir. Nat. Rev. Drug Discovery 4, 955-956 (2005).</Citation></Reference><Reference><Citation>Chan-Tack, K.M., Struble, K.A. & Birnkrant, D.B. Intracranial hemorrhage and liver-associated deaths associated with tipranavir/ritonavir: review of cases from the FDA's Adverse Event Reporting System. AIDS Patient Care STDS 22, 843-850 (2008).</Citation></Reference><Reference><Citation>Hirani, V.N., Raucy, J.L. & Lasker, J.M. Conversion of the HIV protease inhibitor nelfinavir to a bioactive metabolite by human liver CYP2C19. Drug Metab. Dispos. 32, 1462-1467 (2004).</Citation></Reference><Reference><Citation>Zhang, K.E. et al. Circulating metabolites of the human immunodeficiency virus protease inhibitor nelfinavir in humans: structural identification, levels in plasma, and antiviral activities. Antimicrob. Agents Chemother. 45, 1086-1093 (2001).</Citation></Reference><Reference><Citation>Motoya, T. et al. Characterization of nelfinavir binding to plasma proteins and the lack of drug displacement interactions. HIV Med. 7, 122-128 (2006).</Citation></Reference><Reference><Citation>King, J.R. & Acosta, E.P. Tipranavir. Clin. Pharmacokinet. 45, 665-682 (2006).</Citation></Reference><Reference><Citation>Markowitz, M. et al. Long-term efficacy and safety of tipranavir boosted with ritonavir in HIV-1-infected patients failing multiple protease inhibitor regimens: 80-week data from a phase 2 study. J. Acquir. Immune Defic. Syndr. 45, 401-410 (2007).</Citation></Reference><Reference><Citation>Justice, A.C. et al. Drug toxicity, HIV progression, or comorbidity of aging: does tipranavir use increase the risk of intracranial hemorrhage? Clin. Infect. Dis. 47, 1226-1230 (2008).</Citation></Reference><Reference><Citation>Unis, G. et al. Mitochondrial mechanisms of nelfinavir toxicity in human brain microvascular endothelial cells. The FASEB Journal 30, 953.4-.4 (2016).</Citation></Reference><Reference><Citation>Lovegrove, F.E. & Kain, K.C. Chapter 6 - malaria prevention. In: The Travel and Tropical Medicine Manual.4th ed. (eds. Jong, E.C. & Sanford, C.) 76-99 (W.B. Saunders, Edinburgh, 2008).</Citation></Reference><Reference><Citation>de Kock, M. et al. Pharmacokinetics of sulfadoxine and pyrimethamine for intermittent preventive treatment of malaria during pregnancy and after delivery. CPT Pharmacometrics Syst. Pharmacol. 6, 430-438 (2017).</Citation></Reference><Reference><Citation>Amici, C., La Frazia, S., Brunelli, C., Balsamo, M., Angelini, M. & Santoro, M.G. Inhibition of viral protein translation by indomethacin in vesicular stomatitis virus infection: role of eIF2alpha kinase PKR. Cell Microbiol. 17, 1391-1404 (2015).</Citation></Reference><Reference><Citation>Nalamachu, S. & Wortmann, R. Role of indomethacin in acute pain and inflammation management: a review of the literature. Postgrad. Med. 126, 92-97 (2014).</Citation></Reference><Reference><Citation>Pober, J.S. & Sessa, W.C. Evolving functions of endothelial cells in inflammation. Nat. Rev. Immunol. 7, 803-815 (2007).</Citation></Reference><Reference><Citation>Zhang, R. et al. Tumor-associated inflammatory microenvironment in non-small cell lung cancer: correlation with FGFR1 and TLR4 expression via PI3K/Akt pathway. J. Cancer 10, 1004-1012 (2019).</Citation></Reference><Reference><Citation>Geary, T.G., Divo, A.D., Jensen, J.B., Zangwill, M. & Ginsburg, H. Kinetic modelling of the response of Plasmodium falciparum to chloroquine and its experimental testing in vitro. Implications for mechanism of action of and resistance to the drug. Biochem. Pharmacol. 40, 685-691 (1990).</Citation></Reference><Reference><Citation>Pugin, J., Dunn-Siegrist, I., Dufour, J., Tissieres, P., Charles, P.E. & Comte, R. Cyclic stretch of human lung cells induces an acidification and promotes bacterial growth. Am. J. Respir. Cell Mol. Biol. 38, 362-370 (2008).</Citation></Reference><Reference><Citation>Drachman, N., Kadlecek, S., Pourfathi, M., Xin, Y., Profka, H. & Rizi, R. In vivo pH mapping of injured lungs using hyperpolarized [1-(13) C]pyruvate. Magn. Reson. Med. 78, 1121-1130 (2017).</Citation></Reference><Reference><Citation>Ginsburg, H., Nissani, E. & Krugliak, M. Alkalinization of the food vacuole of malaria parasites by quinoline drugs and alkylamines is not correlated with their antimalarial activity. Biochem. Pharmacol. 38, 2645-2654 (1989).</Citation></Reference><Reference><Citation>Vanderkooi, G., Prapunwattana, P. & Yuthavong, Y. Evidence for electrogenic accumulation of mefloquine by malarial parasites. Biochem. Pharmacol. 37, 3623-3631 (1988).</Citation></Reference><Reference><Citation>Fitch, C.D., Chevli, R. & Gonzalez, Y. Chloroquine-resistant Plasmodium falciparum: effect of substrate on chloroquine and amodiaquin accumulation. Antimicrob. Agents Chemother. 6, 757-762 (1974).</Citation></Reference><Reference><Citation>Ritchie, E.C., Block, J. & Nevin, R.L. Psychiatric side effects of mefloquine: applications to forensic psychiatry. J. Am. Acad. Psychiatry Law 41, 224-235 (2013).</Citation></Reference><Reference><Citation>Gonzalez, D., Schmidt, S. & Derendorf, H. Importance of relating efficacy measures to unbound drug concentrations for anti-infective agents. Clin. Microbiol. Rev. 26, 274-288 (2013).</Citation></Reference><Reference><Citation>Fox, L.M. & Saravolatz, L.D. Nitazoxanide: a new thiazolide antiparasitic agent. Clin. Infect. Dis. 40, 1173-1180 (2005).</Citation></Reference><Reference><Citation>la Porte, C.J., Sabo, J.P., Beique, L. & Cameron, D.W. Lack of effect of efavirenz on the pharmacokinetics of tipranavir-ritonavir in healthy volunteers. Antimicrob. Agents Chemother. 53, 4840-4844 (2009).</Citation></Reference><Reference><Citation>Kruse, G. et al. The steady-state pharmacokinetics of nelfinavir in combination with tenofovir in HIV-infected patients. Antivir. Ther. 10, 349-355 (2005).</Citation></Reference><Reference><Citation>Rainsford, K.D. et al. Effects of misoprostol on the pharmacokinetics of indomethacin in human volunteers. Clin. Pharmacol. Ther. 51, 415-421 (1992).</Citation></Reference><Reference><Citation>Burger, D.M., Agarwala, S., Child, M., Been-Tiktak, A., Wang, Y. & Bertz, R. Effect of rifampin on steady-state pharmacokinetics of atazanavir with ritonavir in healthy volunteers. Antimicrobial Agents Chemother. 50, 3336-3342 (2006).</Citation></Reference><Reference><Citation>Tett, S.E., Cutler, D.J., Beck, C. & Day, R.O. Concentration-effect relationship of hydroxychloroquine in patients with rheumatoid arthritis-a prospective, dose ranging study. J. Rheumatol. 27, 1656-1660 (2000).</Citation></Reference><Reference><Citation>Shida, Y., Takahashi, N., Nohda, S. & Hirama, T. Pharmacokinetics and pharmacodynamics of eltrombopag in healthy Japanese males. Jpn. J. Clin. Pharmacol. Ther. 42, 11-20 (2011).</Citation></Reference><Reference><Citation>US Food and Drug Administration (FDA). Abbott L. Clinical Pharmacology and Biopharmaceutics review of Kaletra oral solution (NDA#021251). (2020). Accessed April 13, 2020.</Citation> </Reference><Reference><Citation>Na-Bangchang, K., Limpaibul, L., Thanavibul, A., Tan-Ariya, P. & Karbwang, J. The pharmacokinetics of chloroquine in healthy Thai subjects and patients with Plasmodium vivax malaria. Br. J. Clin. Pharmacol. 38, 278-281 (1994).</Citation></Reference><Reference><Citation>Krudsood, S. et al. New fixed-dose artesunate-mefloquine formulation against multidrug-resistant Plasmodium falciparum in adults: a comparative phase iib safety and pharmacokinetic study with standard-dose nonfixed artesunate plus mefloquine. Antimicrob. Agents Chemother. 54, 3730-3737 (2010).</Citation></Reference><Reference><Citation>Liu, P., Ruhnke, M., Meersseman, W., Paiva, J.A., Kantecki, M. & Damle, B. Pharmacokinetics of anidulafungin in critically ill patients with candidemia/invasive candidiasis. Antimicrob. Agents Chemother. 57, 1672-1676 (2013).</Citation></Reference><Reference><Citation>Raja, A., Lebbos, J. & Kirkpatrick, P. Atazanavir sulphate. Nat. Rev. Drug Discov. 2, 857-858 (2003).</Citation></Reference><Reference><Citation>Harrison, T.S. & Scott, L.J. Atazanavir. Drugs 65, 2309-2336 (2005).</Citation></Reference><Reference><Citation>Murdoch, D. & Plosker, G.L. Anidulafungin. Drugs 64, 2249-2258 (2004).</Citation></Reference><Reference><Citation>Goel, P. & Gerriets, V. Chloroquine. In: StatPearls. (StatPearls Publishing, Treasure Island (FL). https://www.ncbi.nlm.nih.gov/books/NBK551512/ 2020.</Citation></Reference><Reference><Citation>Garnock-Jones, K.P. Eltrombopag. Drugs 71, 1333-1353 (2011).</Citation></Reference><Reference><Citation>Pharmaceuticals and Medical Devices Agency (PMDA). Report on the Deliberation Results. (2014).</Citation> </Reference><Reference><Citation>Ben-Zvi, I., Kivity, S., Langevitz, P. & Shoenfeld, Y. Hydroxychloroquine: from malaria to autoimmunity. Clin. Rev. Allergy Immunol. 42, 145-153 (2012).</Citation></Reference><Reference><Citation>Yeh, K.C. Pharmacokinetic overview of indomethacin and sustained-release indomethacin. Am. J. Med. 79, 3-12 (1985).</Citation></Reference><Reference><Citation>Corbett, A.H., Lim, M.L. & Kashuba, A.D. Kaletra (lopinavir/ritonavir). Ann. Pharmacother. 36, 1193-1203 (2002).</Citation></Reference><Reference><Citation>Price, R.N. et al. Artesunate/mefloquine treatment of multi-drug resistant falciparum malaria. Trans. R Soc. Trop. Med. Hyg. 91, 574-577 (1997).</Citation></Reference><Reference><Citation>McHutchison, J.G. et al. A randomized, double-blind, placebo-controlled dose-escalation trial of merimepodib (VX-497) and interferon-alpha in previously untreated patients with chronic hepatitis C. Antivir. Ther. 10, 635-643 (2005).</Citation></Reference><Reference><Citation>James, J.S. Nelfinavir (Viracept) approved: fourth protease inhibitor available. AIDS Treat. News 267, 1-2 (1997).</Citation></Reference><Reference><Citation>Chen, W., Mook, R.A., Premont, R.T. & Wang, J. Niclosamide: beyond an antihelminthic drug. Cell. Signal. 41, 89-96 (2018).</Citation></Reference><Reference><Citation>Anderson, V.R. & Curran, M.P. Nitazoxanide. Drugs 67, 1947-1967 (2007).</Citation></Reference><Reference><Citation>Porche, D.J. Ritonavir (Norvir). J. Assoc. Nurses AIDS Care 8, 81-83 (1997).</Citation></Reference><Reference><Citation>Miller, K.D., Lobel, H.O., Satriale, R.F., Kuritsky, J.N., Stern, R. & Campbell, C.C. Severe cutaneous reactions among American travelers using pyrimethamine-sulfadoxine (Fansidar) for malaria prophylaxis. Am. J. Trop. Med. Hyg. 35, 451-458 (1986).</Citation></Reference><Reference><Citation>Orman, J.S. & Perry, C.M. Tipranavir: a review of its use in the management of HIV infection. Drugs 68, 1435-1463 (2008).</Citation></Reference></ReferenceList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/CovidChloroV1/Data/Main/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 001621 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Corpus/biblio.hfd -nk 001621 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= CovidChloroV1
|flux= Main
|étape= Corpus
|type= RBID
|clé= pubmed:32438446
|texte= Prioritization of Anti-SARS-Cov-2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics.
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Corpus/RBID.i -Sk "pubmed:32438446" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Main/Corpus/biblio.hfd \
| NlmPubMed2Wicri -a CovidChloroV1
| This area was generated with Dilib version V0.6.38. |  |