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. 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 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..