Background: The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) first broke out in Wuhan (China) and subsequently spread worldwide. Chloroquine has been sporadically used in treating SARS-CoV-2 infection. Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions. We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late-phase in critically ill SARS-CoV-2 infected patients. Currently, there is no evidence to support the use of hydroxychloroquine in SARS-CoV-2 infection.
Methods: The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2 infected Vero cells. Physiologically-based pharmacokinetic models (PBPK) were implemented for both drugs separately by integrating their in vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen whilst considering the drug's safety profile.
Results: Hydroxychloroquine (EC50=0.72 μM) was found to be more potent than chloroquine (EC50=5.47 μM) in vitro. Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection, as it reached three times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance.
Conclusions: Hydroxychloroquine was found to be more potent than chloroquine to inhibit SARS-CoV-2 in vitro.
Keywords: Chloroquine; Hydroxychloroquine; SARS-CoV-2.
© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.
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In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine.Biochem Biophys Res Commun. 2004 Oct 8;323(1):264-8. doi: 10.1016/j.bbrc.2004.08.085. Biochem Biophys Res Commun. 2004. PMID: 15351731 Free PMC article.
Chloroquine is a potent inhibitor of SARS coronavirus infection and spread.Virol J. 2005 Aug 22;2:69. doi: 10.1186/1743-422X-2-69. Virol J. 2005. PMID: 16115318 Free PMC article.
Broad-spectrum coronavirus antiviral drug discovery.Expert Opin Drug Discov. 2019 Apr;14(4):397-412. doi: 10.1080/17460441.2019.1581171. Epub 2019 Mar 8. Expert Opin Drug Discov. 2019. PMID: 30849247 Review.
SARS-CoV replication and pathogenesis in an in vitro model of the human conducting airway epithelium.Virus Res. 2008 Apr;133(1):33-44. doi: 10.1016/j.virusres.2007.03.013. Epub 2007 Apr 23. Virus Res. 2008. PMID: 17451829 Free PMC article. Review.