Pharmacokinetic modelling to estimate intracellular favipiravir ribofuranosyl-5′-triphosphate exposure to support posology for SARS-CoV-2

Objectives: Favipiravir has discrepant activity against SARS-CoV-2 in vitro, concerns about teratogenicity and pill burden, and an unknown optimal dose. This analysis used available data to simulate the intracellular pharmacokinetics of the favipiravir active metabolite [favipiravir ribofuranosyl-5'-triphosphate (FAVI-RTP)]. Methods: Published in vitro data for intracellular production and elimination of FAVI-RTP in Madin-Darby canine kidney cells were fitted with a mathematical model describing the time course of intracellular FAVI-RTP as a function of favipiravir concentration. Parameter estimates were then combined with a published population pharmacokinetic model in Chinese patients to predict human intracellular FAVI-RTP. In vitro FAVI-RTP data were adequately described as a function of concentrations with an empirical model, noting simplification and consolidation of various processes and several assumptions. Results: Parameter estimates from fittings to in vitro data predict a flatter dynamic range of peak to trough for intracellular FAVI-RTP (peak to trough ratio of similar to 1 to 1) when driven by a predicted free plasma concentration profile, compared with the plasma profile of parent favipiravir (ratio of similar to 2 to 1). This approach has important assumptions, but indicates that, despite rapid clearance of the parent from plasma, sufficient intracellular FAVI-RTP may be maintained across the dosing interval because of its long intracellular half-life. Conclusions: Population mean intracellular FAVI-RTP concentrations are estimated to be maintained above the Km for the SARS-CoV-2 polymerase for 9 days with a 1200 mg twice-daily regimen (following a 1600 mg twice-daily loading dose on day 1). Further evaluation of favipiravir as part of antiviral combinations for SARS-CoV-2 is warranted.

Automated summary

This study utilized a mathematical model to simulate the intracellular pharmacokinetics of the active metabolite of favipiravir, revealing that despite rapid clearance of the parent drug from plasma, sufficient intracellular active metabolite may be maintained across the dosing interval. The predicted regimen of 1200 mg twice daily of favipiravir is estimated to maintain intracellular active metabolite concentrations above the Km for the SARS-CoV-2 polymerase for 9 days. Further evaluation of favipiravir in combination with other antivirals for SARS-CoV-2 treatment is recommended.