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)
Xueting Yao, Fei Ye, Miao Zhang, Cheng Cui, Baoying Huang, Peihua Niu, Xu Liu, Li Zhao, Erdan Dong, Chunli Song, Siyan Zhan, Roujian Lu, Haiyan Li, Wenjie Tan, Dongyang Liu
Clinical Infectious Diseases, doi:10.1093/cid/ciaa237
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 (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 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.
Suggested Dosing Regimens for Hydroxychloroquine to Treat SARS-CoV-2 Infection The free lung trough concentrations were also projected from the simulations. The R LTEC under the different dosing regimens is shown in Table 1 . The R LTEC values of hydroxychloroquine were found to be higher than the R LTEC values of chloroquine on days 1, 3, 5, and 10. This suggests that hydroxychloroquine may achieve ideal clinical efficacy under the simulated dosing regimens. The R LTEC on day 1 was notably higher for hydroxychloroquine than for chloroquine. This is likely due to the loading dose of
Supplementary Data Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. Financial support. This work was supported by the "13th Five-Year" National Major New Drug Projects of China, Ministry of Science and Technology of the People's Republic of China (grant number 2017ZX09101001-002-001) and the Bill & Melinda Gates Foundation (grant number OPP1204780).
Notes
Acknowledgments. The authors thank Potential conflicts of interest. C. S., H. L., and D. L. have patents pending for antimicrobial infection pharmoceutical composition and its application. All other authors report no potential conflicts. All authors have submitted the..
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'abstract': '<jats:title>Abstract</jats:title>\n'
' <jats:sec>\n'
' <jats:title>Background</jats:title>\n'
' <jats:p>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.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Methods</jats:title>\n'
' <jats:p>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.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Results</jats:title>\n'
' <jats:p>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 '
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'advance.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Conclusions</jats:title>\n'
' <jats:p>Hydroxychloroquine was found to be more potent than chloroquine to '
'inhibit SARS-CoV-2 in vitro.</jats:p>\n'
' </jats:sec>',
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