Estimation of SARS-CoV-2 Viral Dynamics Parameters in Favipiravir-Treated Cynomolgus Macaques: Comparison of Individual and Group Average Model Fitting

Favipiravir, an antiviral that inhibits viral RNA-dependent RNA polymerase, has demonstrated promise as a therapeutic for RNA viral infections such as SARS-CoV-2. Mathematical modeling of viral kinetics provides a tool for analyzing the progression of viral infections and the action of antiviral drugs. In the present investigation, the viral kinetics of SARS-CoV-2 infection in cynomolgus macaques treated with the antiviral drug favipiravir were analyzed using a target-cell-limited mathematical model of viral infection. The model parameters were estimated by fitting the model independently to each of the 30 individual animals across four treatment groups (untreated control, 100 mg/kg, 150 mg/kg, and 180 mg/kg). Bootstrap resampling was applied to quantify the parameter uncertainty, and Mann–Whitney U tests were used to compare the group-level parameter estimates between the control and each treated group. Despite broad trends in several parameters, no statistically significant differences were detected between the control and any favipiravir-dose group. We also fit the model to the group-averaged viral titer curves, which led to statistically significant differences in some of the parameters. These results highlight the danger in using averaged viral titers when there is substantial inter-animal variability in individual viral kinetics data, and they suggest that larger cohorts may be required to detect drug effects with statistical confidence at the individual animal level.