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)
et al., Clin. Infect. Dis., 2020 Mar 9, doi:10.1093/cid/ciaa237, Mar 2020
HCQ for COVID-19
1st treatment shown to reduce risk in
March 2020, now with p < 0.00000000001 from 424 studies, used in 59 countries.
No treatment is 100% effective. Protocols
combine treatments.
6,200+ studies for
200+ treatments. c19early.org
|
In vitro study showing that HCQ is more potent than CQ in vitro for inhibiting SARS-CoV-2. Simulates HCQ concentration in lung fluid and provides dosing recommendations.
39 preclinical studies support the efficacy of HCQ for COVID-19:
3.
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12.
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13.
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14.
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15.
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18.
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19.
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20.
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24.
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33.
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34.
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35.
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36.
Yao 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 Mar 9, doi:10.1093/cid/ciaa237.
Yao et al., 9 Mar 2020, peer-reviewed, 16 authors.
In vitro studies are an important part of preclinical research, however results may be very different in vivo.
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, 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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