Finding the Dose for Hydroxychloroquine Prophylaxis for COVID‐19: The Desperate Search for Effectiveness
Mahmoud Al‐kofahi, Pamala Jacobson, David R Boulware, Arthur Matas, Raja Kandaswamy, Mutaz M Jaber, Radha Rajasingham, Jo‐anne H Young, Melanie R Nicol
Clinical Pharmacology & Therapeutics, doi:10.1002/cpt.1874
Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Hydroxychloroquine is currently of interest for treatment and prevention of coronavirus disease 2019 (COVID-19). In the absence of therapeutic efficacy targets, optimal dosing is unknown.
WHAT QUESTION DID THIS STUDY ADDRESS? We examined various hydroxychloroquine dosing strategies and compared predicted plasma exposures to in vitro efficacy targets.
WHAT DOES THIS STUDY ADD TO OUR KNOW-LEDGE? Conventional malaria prevention and treatment dosing may not be sufficient to reach plasma concentrations that would be expected to inhibit or suppress severe acute respiratory syndrome coronavirus 2. HOW MIGHT THIS CHANGE CLINICAL PHARMA-COLOGY OR TRANSLATIONAL SCIENCE? These findings are intended to guide the research community in optimizing dose selection for COVID-19 prevention and early treatment trials.
SUPPORTING INFORMATION Supplementary information accompanies this paper on the Clinical Pharmacology & Therapeutics website (www.cpt-journal.com).
FUNDING Support for this study was received from the National Institute of Allergy and Infectious Diseases (K08 AI134262 for M.R.N.); (R01AI140303 for P.A.J.); and (U01AI125003 for D.R.B.).
CONFLICT OF INTEREST The authors declared no competing interests for this work.
AUTHOR CONTRIBUTIONS
References
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"abstract": "<jats:p>Hydroxychloroquine is an antimalarial drug being tested as a potential treatment for the novel coronavirus disease 2019 (COVID‐19) pandemic caused by the severe acute respiratory syndrome coronavirus 2. Although the efficacy of hydroxychloroquine for COVID‐19 remains uncertain, it may serve as a potential prophylactic agent especially in those at high risk, such as healthcare workers, household contacts of infected patients, and the immunocompromised. Our aim was to identify possible hydroxychloroquine dosing regimens through simulation in those at high risk of infections by optimizing exposures above the <jats:italic>in vitro</jats:italic> generated half maximal effective concentration (EC<jats:sub>50</jats:sub>) and to help guide researchers in dose‐selection for COVID‐19 prophylactic studies. To maintain weekly troughs above EC<jats:sub>50</jats:sub> in > 50% of subjects at steady‐state in a pre‐exposure prophylaxis setting, an 800 mg loading dose followed by 400 mg twice or 3 times weekly is required. In an exposure driven, post‐exposure prophylaxis setting, 800 mg loading dose followed in 6 hours by 600 mg, then 600 mg daily for 4 more days achieved daily troughs above EC<jats:sub>50</jats:sub> in > 50% subjects. These doses are higher than recommended for malaria chemoprophylaxis, and clinical trials are needed to establish safety and efficacy.</jats:p>",
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