Remdesivir-Ivermectin combination displays synergistic interaction with improved in vitro antiviral activity against SARS-CoV-2

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Drug combination strategies of repurposed drugs offer a number of advantages to monotherapies including the potential to achieve greater efficacy, the potential to increase the therapeutic index of drugs and the potential to reduce the emergence of drug resistance. Combination of agents with antiviral mechanisms of action with immune-modulatory or anti-inflammatory drug is also worthy of investigation. The in vitro synergistic interaction between two FDA approved drugs, remdesivir and ivermectin resulted in enhanced antiviral activity against SARS-CoV-2, the causative pathogen of COVID-19. These findings warrant further investigations into the clinical potential of this combination, together with studies to define the underlying mechanism.

Remdesivir is a prodrug C-adenosine nucleoside analog that inhibits the viral RNA-dependent, RNA polymerase and which is formulated by using sulfobutyl ether beta-cyclodextrin (SBECD) as solubilizer. Ivermectin is an FDA-approved anti-parasitic drug.

Dose-effect relationship for the inhibition (%) of SARS-CoV-2 cytopathic activity for both drugs was studied on VERO E6 cells infected by SARS-CoV-2. The measured EC50 for ivermectin was 2.3 ± 1.0 µM and EC50 for remdesivir was 1.9 ± 1.4 µM. These values closely match those reported in recent studies for both drugs. Subsequent determination of the IVM-RDV combination interaction using isobologram analysis revealed a FICI<=0.5 indicating a synergistic interaction (Fig. 1).

Figure 1. Isobologram showing interactions between Remdesivir and Ivermectin.

Jeffreys et al. (2020) Remdesivir-Ivermectin combination displays synergistic interaction with improved in
vitro antiviral activity against SARS-CoV-2. bioRxiv preprint doi: https://doi.org/10.1101/2020.12.23.424232

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