Finding the Dose for Hydroxychloroquine Prophylaxis for COVID-19: The Desperate Search for Effectiveness
Al-Kofahi et al.
, Finding the Dose for Hydroxychloroquine Prophylaxis for COVID-19: The Desperate Search for Effectiveness
, Clin. Pharmacol. Ther., Jun 1, 2020, doi:10.1002/cpt.1874
Analysis of HCQ dosing regimens, recommending:
PrEP: 800mg loading dose followed by 400mg 2 or 3 times weekly to maintain weekly troughs above EC50
in >50% of patients at steady-state.
PEP: 800mg loading dose followed in 6 hours by 600mg, then 600mg daily for 4 more days to achieve daily troughs above EC50
in >50% subjects.
Al-Kofahi et al., 1 Jun 2020, peer-reviewed, 9 authors.
Abstract: BRIEF REPORT
Finding the Dose for Hydroxychloroquine
Prophylaxis for COVID-19: The Desperate
Search for Effectiveness
Mahmoud Al-Kofahi1, Pamala Jacobson1, David R. Boulware2, Arthur Matas3, Raja Kandaswamy3,
Mutaz M. Jaber1, Radha Rajasingham2, Jo-Anne H. Young2 and Melanie R. Nicol1,*
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 in vitro generated half maximal effective
concentration (EC50) and to help guide researchers in dose-selection for COVID-19 prophylactic studies. To
maintain weekly troughs above EC50 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, postexposure 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 EC50 in > 50% subjects. These doses are higher than recommended for malaria
chemoprophylaxis, and clinical trials are needed to establish safety and efficacy.
WHAT IS THE CURRENT KNOWLEDGE ON THE
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
WHAT QUESTION DID THIS STUDY ADDRESS?
We examined various hydroxychloroquine dosing strategies
and compared predicted plasma exposures to in vitro efficacy
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
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 PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
These findings are intended to guide the research community in optimizing dose selection for COVID-19 prevention
and early treatment trials.
The rapidly progressing coronavirus disease 2019 (COVID19) pandemic has led to overwhelming interest in treatment
and prevention therapeutics. There is no approved therapy for
COVID-19, and a number of trials have been initiated, including
hydroxychloroquine, losartan, remdesivir, tocilizumab, intravenous immunoglobulin, and convalescent plasma.1 There are > 100
recruiting or not yet recruiting treatment studies listed on clinicaltrials.gov as of March 29, 2020. Although reports have surfaced
regarding the use of chloroquine and hydroxychloroquine, drugs
used in malaria, the efficacy for COVID-19 remains uncertain.
Hydroxychloroquine has known in vitro activity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
virus. However, the half maximal effective concentration (EC50)
for SARS-CoV-2 virus is different than for malaria with a > 20fold higher in vitro EC50 of hydroxychloroquine for SARS-CoV-2
vs. malaria. EC50 values for SARS-CoV-2 virus in the literature
have ranged from 0.72–17.31 μM, with higher EC50..
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