Optimal dosing & time: Issues to get hydroxychloroquine safety & efficacy against COVID-19/SARS-CoV-2

Sir,

Due to its in vitro antiviral characteristics and immunomodulatory properties, chloroquine (CQ) and hydroxychloroquine (HCQ) are candidates for the prevention and treatment of severe acute respiratory syndrome (SARS) for more than a decade1. The coronavirus disease 2019 (COVID-19) pandemic with SARS-CoV-2 renovated its interest, but clinical studies until now showed only a few (if any) benefits from CQ/HCQ in the treatment of COVID-192.

It is important to note that a possible explanation to this failure is based on the pharmacokinetic characteristics of these drugs. CQ and HCQ have large volumes of distribution due to their extensive sequestration by tissues, and therefore, a prolonged time is needed to reach stable plasmatic concentrations (the steady state). Both CQ and HCQ are used as immunomodulatory drugs in the treatment of systemic lupus erythematosus, and clinical improvement is obtained only after some weeks of treatment. This correlates with time to reach steady state. It was estimated that HCQ at a dose of 310 mg/day would take 14 days to reach 90 per cent of the plasma steady state3. Higher daily doses would lead to higher steady-state concentrations and shorten the time to achieve them. However, very high dosage is also associated with increased toxicity4. This pharmacokinetic profile makes CQ/HCQ more suitable for pre-exposure prophylaxis than for the treatment of COVID-19.

Chatterjee et al5 in their case-control study about pre-exposure prophylaxis of COVID-19 with HCQ in healthcare workers demonstrated that HCQ provided significantly additional protection against COVID-19 beginning after four weeks of use of maintenance dose of HCQ 400 mg once weekly, in a progressive dose-response relationship. A single loading dose of HCQ 400 mg twice a day (bid) was also used.

These are encouraging results. Obviously, the use of personal protective equipment (PPE) cannot be neglected (the study shows the highest odds ratio with its use), but we are now able to consider an additional element of protection with HCQ in prophylactic use for those who are in high-risk of infection (healthcare workers).

To contribute to this effort, I additionally suggest the use of HCQ (400 mg bid) on the first day, followed by 400 mg three times a week in the first week, and then the maintenance dose of HCQ 400 mg once weekly. This scheme with a slightly higher loading dose in the first week may warrant earlier clinical benefits (after the first seven days)6. It would be useful for populations who already are at risk of COVID-19 infection, to get faster clinical benefits probably without significant risk of adverse effects.