Population pharmacokinetic/pharmacodynamic modelling to evaluate favipiravir in combination with lopinavir-ritonavir in patients with COVID-19.

AIMS: The repurposed use of favipiravir in COVID-19 has been reported to have limited clinical efficacy, yet it has been widely used in some countries. Favipiravir causes mutagenesis in RNA viruses, and it is currently unknown whether it may have a measurable effect on the virus in humans. In this study, we report the secondary endpoints from the phase 2a randomized, double-blind, 2 × 2 factorial placebo-controlled FLARE trial, which studied the combination of favipiravir and lopinavir-ritonavir.

METHODS

Population pharmacokinetic and viral dynamic models including data from 59 and 235 participants respectively were developed to assess the drug effect of favipiravir in combination with lopinavir-ritonavir. Viral whole-genome sequencing was performed.

RESULTS

The final joint model consisted of a slope-intercept exponential decay viral dynamic model and a one-compartment model with first-order absorption and elimination for favipiravir pharmacokinetics. The mean death rate of infected cells (δ) was 0.96 day-1. Favipiravir mean apparent clearance (CL/F) and mean apparent volume of distribution were 1.73 L/h and 22.1 L, respectively. Favipiravir co-administration with lopinavir-ritonavir increased CL/F by twofold, representing an unexpected drug-drug interaction. Favipiravir and lopinavir-ritonavir drug effects on δ did not improve model fit in the final joint model, indicating that neither drug has any antiviral effect against SARS-CoV-2. Viral sequencing did not show a clear mutagenic signature.

CONCLUSIONS

Our findings suggest that favipiravir does not have antiviral activity at the dose used in our study, and further work to understand the mechanistic basis of the drug-drug interaction with lopinavir-ritonavir is required.