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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).
Clin Infect Dis. 2020 07 28; 71(15):732-739.CI

Abstract

BACKGROUND

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first broke out in 2019 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 patients with SARS-CoV-2. 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 (PBPK) models 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 while 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 3 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.

Authors+Show Affiliations

Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China.Department of Orthopedics, Peking University Third Hospital, Beijing, China.Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, China.NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China. Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China.NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32150618

Citation

Yao, Xueting, 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)." Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America, vol. 71, no. 15, 2020, pp. 732-739.
Yao X, Ye F, Zhang M, 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. 2020;71(15):732-739.
Yao, X., Ye, F., Zhang, M., Cui, C., Huang, B., Niu, P., Liu, X., Zhao, L., Dong, E., Song, C., Zhan, S., Lu, R., Li, H., Tan, W., & Liu, D. (2020). 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). Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America, 71(15), 732-739. https://doi.org/10.1093/cid/ciaa237
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. 2020 07 28;71(15):732-739. PubMed PMID: 32150618.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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). AU - Yao,Xueting, AU - Ye,Fei, AU - Zhang,Miao, AU - Cui,Cheng, AU - Huang,Baoying, AU - Niu,Peihua, AU - Liu,Xu, AU - Zhao,Li, AU - Dong,Erdan, AU - Song,Chunli, AU - Zhan,Siyan, AU - Lu,Roujian, AU - Li,Haiyan, AU - Tan,Wenjie, AU - Liu,Dongyang, PY - 2020/02/25/received PY - 2020/03/12/accepted PY - 2020/3/10/pubmed PY - 2020/8/11/medline PY - 2020/3/10/entrez KW - SARS-CoV-2 KW - chloroquine KW - hydroxychloroquine SP - 732 EP - 739 JF - Clinical infectious diseases : an official publication of the Infectious Diseases Society of America JO - Clin. Infect. Dis. VL - 71 IS - 15 N2 - BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first broke out in 2019 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 patients with SARS-CoV-2. 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 (PBPK) models 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 while 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 3 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. SN - 1537-6591 UR - https://www.unboundmedicine.com/medline/citation/32150618/full_citation L2 - https://academic.oup.com/cid/article-lookup/doi/10.1093/cid/ciaa237 DB - PRIME DP - Unbound Medicine ER -