The Approved Dose of Ivermectin Alone is not the Ideal Dose for the Treatment of COVID-19

Abstract

Caly et al.¹ reported that ivermectin inhibited severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) in vitro for up to 48 hours using ivermectin at 5 μM. The concentration resulting in 50% inhibition (IC₅₀ ; 2 µM) was > 35× higher than the maximum plasma concentration (C_max ) after oral administration of the approved dose of ivermectin when given fasted. Simulations were conducted using an available population pharmacokinetic model to predict total (bound and unbound) and unbound plasma concentration-time profiles after a single and repeat fasted administration of the approved dose of ivermectin (200 μg/kg), 60 mg, and 120 mg. Plasma total C_max was determined and then multiplied by the lung:plasma ratio reported in cattle to predict the lung C_max after administration of each single dose. Plasma ivermectin concentrations of total (bound and unbound) and unbound concentrations do not reach the IC₅₀ , even for a dose level 10× higher than the approved dose. Even with the high lung:plasma ratio, ivermectin is unlikely to reach the IC₅₀ in the lungs after single oral administration of the approved dose (predicted lung: 0.0873 µM) or at doses 10× higher that the approved dose administered orally (predicted lung: 0.820 µM). In summary, the likelihood of a successful clinical trial using the approved dose of ivermectin is low. Combination therapy should be evaluated in vitro. Repurposing drugs for use in coronavirus disease 2019 (COVID-19) treatment is an ideal strategy but is only feasible when product safety has been established and experiments of repurposed drugs are conducted at clinically relevant concentrations.

Figure 1

Total (bound and unbound) and unbound plasma ivermectin concentrations over time relative to the 50% inhibition (IC₅₀) after approved doses of ivermectin (200 µg/kg) administered once weekly (instead of as a single dose), and after higher doses, including 60 mg every 3 days or 120 mg once weekly. Red dashed line = IC₅₀ reported by Caly et al. (2020), 2 µM (1750 ng/mL). Blue shaded area and line = total plasma drug concentration and its 95% confidence interval (CI); red shaded area and line = free plasma drug concentration and its 95% CI.