Why Certain Repurposed Drugs Are Unlikely to Be Effective Antivirals to Treat SARS-CoV-2 Infections
2024
Selwyn J. Hurwitz | Ramyani De | Julia C. LeCher | Jessica A. Downs-Bowen | Shu Ling Goh | Keivan Zandi | Tamara McBrayer | Franck Amblard | Dharmeshkumar Patel | James J. Kohler | Manoj Bhasin | Brian S. Dobosh | Vikas Sukhatme | Rabindra M. Tirouvanziam | Raymond F. Schinazi
Most repurposed drugs have proved ineffective for treating COVID-19. We evaluated median effective and toxic concentrations (EC<sub>50</sub>, CC<sub>50</sub>) of 49 drugs, mostly from previous clinical trials, in Vero cells. Ratios of reported unbound peak plasma concentrations, (C<sub>max</sub>)/EC<sub>50</sub>, were used to predict the potential in vivo efficacy. The 20 drugs with the highest ratios were retested in human Calu-3 and Caco-2 cells, and their CC<sub>50</sub> was determined in an expanded panel of cell lines. Many of the 20 drugs with the highest ratios were inactive in human Calu-3 and Caco-2 cells. Antivirals effective in controlled clinical trials had unbound C<sub>max</sub>/EC<sub>50</sub> ≥ 6.8 in Calu-3 or Caco-2 cells. EC<sub>50</sub> of nucleoside analogs were cell dependent. This approach and earlier availability of more relevant cultures could have reduced the number of unwarranted clinical trials.
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