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      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)

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          Abstract

          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 (EC 50=0.72 μM) was found to be more potent than chloroquine (EC 50=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.

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          Author and article information

          Journal
          Clin Infect Dis
          Clin. Infect. Dis
          cid
          Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
          Oxford University Press (US )
          1058-4838
          1537-6591
          09 March 2020
          09 March 2020
          Affiliations
          [1 ] Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China
          [2 ] MHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention,  China CDC, Beijing, China
          [3 ] Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China
          [4 ] Department of Orthopedics, Peking University Third Hospital, Beijing, China
          [5 ] Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, China
          Author notes
          Corresponding author: Dongyang Liu, Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China. ( liudongyang@ 123456sina.vip.com )

          Xueting Yao, Fei Ye, Miao Zhang, Cheng Cui and Baoyin Huang contributed equally

          Dongyang Liu, Wenjie Tan and Haiyan Li contributed equally

          Article
          ciaa237
          10.1093/cid/ciaa237
          7108130
          32150618
          © The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.

          This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

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          Categories
          Major Article
          AcademicSubjects/MED00290
          Custom metadata
          PAP
          accepted-manuscript

          Infectious disease & Microbiology

          hydroxychloroquine, sars-cov-2, chloroquine

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