In a recent study published in PLoS ONE, researchers assessed the impact of drug combinations on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suppression.
While new antivirals against SARS-CoV-2 are being approved, they have significant limitations and are not recommended for hospitalized coronavirus disease 2019 (COVID-19) patients with limited antiviral therapeutic choices.
Repurposed medications have demonstrated controversial therapeutic effects in the past, and it is difficult to comprehend why certain trials have produced excellent results while others have failed.
About the study
In the present study, researchers assessed the effect of different antiviral drug combinations to suppress SARS-CoV-2 completely in the lungs of COVID-19 patients.
From over 100 research papers detailing at least one medication candidate with the potential to inhibit SARS-CoV-2, 26 drug candidates having well-documented antiviral efficacy were selected. Each medication was evaluated for cytotoxicity as well as antiviral activity as a monotherapy using the 2019-nCoV/ItalyINMI1 SARS-CoV-2 strain, and ten were selected because their therapeutic index (TI) was more than 1. These selected compounds included: azithromycin, camostat, darunavir, homoharringtonine, hydroxychloroquine, ivermectin, lopinavir, nitazoxanide, remdesivir, and umifenovir.
The team analyzed all putative double combinations of the selected antivirals using the following criteria: (1) the highest concentration that exhibited 0% cytotoxicity (HCC0), (2) the lowest 100% inhibitory concentration (LIC100), and (3) the estimation of synergy using a stringent and well-established model. The pursuit of optimum safety and antiviral efficiency in vivo necessitated a precise search for combinations with zero cytotoxicity and 100% viral suppression in vitro. As remdesivir (RDV) was the sole approved anti-SARS-CoV-2 medication among the selected antivirals, the team investigated the possible synergies of RDV-based double combinations.
When there was no antagonism, azithromycin (AZI) and ivermectin (IVM) inhibited SARS-CoV-2 replication synergistically with RDV. The AZI and RDV synergistic combination resulted in a significant increase in potency, as evidenced by a reduction in LIC100, indicating that a significantly lesser concentration of each drug by almost four- and 12-times for AZI and RDV, respectively, was required to completely inhibit viral replication when the drugs were used together as opposed to when they were used individually.
For respiratory viral disease treatments, including SARS-CoV-2 therapy, the concentration of the drug in the lungs is the most important factor. As RDV is a prodrug, it is insufficient to assess its pharmacokinetics (PK) in plasma. Nucleoside triphosphate form (NucTP) is the active form of RDV, accumulating intracellularly in the lung at a concentration of 4 to 10 µM following intravenous injection of 200 mg RDV.
The half-maximal inhibitory concentration (IC50) and IC90 concentrations of Nuc-TP in the lung were 7.7 µM and 17.6 µM, respectively. This explained the varying efficacy of RDV, as hospitalized patients were treated with a suboptimal concentration of Nuc-TP, which could only inhibit 50% of SARS-CoV-2 replication. In vitro, the LIC100 corresponding to RDV monotherapy was 2.1 µM, which was associated with an estimated Nuc-TP concentration of 21 µM that cannot be achieved in the lung using RDV alone. In contrast, when examined in combination with AZI, the resulting RDV LIC100 declined to 0.6 µM, which corresponded to a Nuc-TP concentration of 6 µM intracellularly in the lung, which was reached following administration of effective RDV dosages. Since the intracellular half-life of Nuc-TP is between 14 and 24 hours, it is anticipated that SARS-CoV-2 would be subjected to therapeutically efficient concentrations for the entire day if this combination therapy is administered.
In vivo, the combination of AZI with RDV enhances the antiviral activity of the AZI to a significant degree. Commonly administered antibiotic dosages of AZI have not demonstrated anti-SARS-CoV-2 activity in humans since the therapeutically effective anti-SARS-CoV-2 concentration cannot be reached in plasma even with doses between 1 to 4 gr AZI administered intravenously.
The IVM and RDV combination also displayed a synergistic rise in anti-SARS-CoV-2 activity, leading to a significant decrease in LIC100. This indicated that a considerably lower concentration of each drug was required to completely inhibit virus replication when drug combinations were used compared to when they were used individually. A combination of RDV with IVM or AZI resulted in therapeutically effective antiviral plasma concentrations of either medication.
Overall, the study findings demonstrated that certain antiviral drugs could be appropriately combined to elicit effective anti-SARS-CoV-2 activity, which is otherwise not noted with monotherapies.