Alterations in favipiravir (T-705) pharmacokinetics and biodistribution in a hamster model of viral hemorrhagic fever

Abstract

Favipiravir (T-705) is a new anti-influenza drug approved for human use in Japan and progressing through Phase 3 clinical trials in the U.S. In addition to its potent inhibitory effects against influenza virus infection, the compound has been shown to be broadly active against RNA viruses from 9 different families, including the Arenaviridae. Several members of the Arenaviridae family of viruses are significant human pathogens that cause viral hemorrhagic fever, a severe systemic syndrome where vascular leak is a cardinal feature. Because arenaviral infections are unlikely to be diagnosed and treated until the illness has progressed to a more advanced state, it is important to understand the effects of the disease state on favipiravir pharmacokinetics (PK) and biodistribution to help guide therapeutic strategy. During acute arenavirus infection in hamsters, we found reduced plasma favipiravir concentrations and altered kinetics of absorption, elimination and time to maximum drug concentration. In addition, the amounts of the favipiravir M1 primary metabolite were higher in the infected animals, suggesting that favipiravir metabolism may favor the formation of this inactive metabolite during viral infection. We also discovered differences in favipiravir and M1 PK parameters associated with arenavirus infection in a number of hamster tissues. Finally, analysis at the individual animal level demonstrated a correlation between reduced plasma favipiravir concentration with increased disease burden as reflected by weight loss and viral load. Our study is the first to show the impact of active viral infection and disease on favipiravir PK and biodistribution, highlighting the need to consider alterations in these parameters when treating individuals with viral hemorrhagic fever of arenavirus or other etiology.

Favipiravir antiviral efficacy against SARS-CoV-2 in a hamster model

“…A good penetration of favipiravir in lungs was observed with lung/plasma ratios ranging from 35 to 44% after repeated doses, consistent with its physicochemical properties. Lung exposure was also in accordance with previous studies 36 .…”

“…Favipiravir PK in our hamster model displayed a non-linear increase in plasma exposure between the doses as already reported in nonhuman primates 35 . The observed favipiravir concentration versus time profiles were in agreement with previous results of a PK study performed in 7-8 week-old hamsters orally treated with a single dose of 100mg/kg of favipiravir 36 . The maximum plasma drug concentration occurred at 0.5 h after oral administration, earlier than in humans, and then decreased rapidly in agreement with its short half-life 37 .…”

Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses

“…First, the studies were conducted in noninfected animals, and infection may alter the drug concentration. For instance, a decrease of the favipiravir concentration was observed in a hamster model of arenavirus hemorrhagic fever (31). Second, the criterion used to propose the dosing regimens was based on the comparison between the EC 50 observed in vitro and the free plasma concentration of favipiravir, which may not be the best marker of nucleoside analogue antiviral activity.…”

Ebola virus dynamics in mice treated with favipiravir

“…This assumption will need to be verified by assessing drug pharmacokinetics during the course of the infection. In particular a study conducted in hamsters has suggested that infection with arenavirus led to lower favipiravir plasma and tissue concentration and that the impairment in pharmacokinetics increased with higher viral load levels (Gowen et al, 2015). Second the viral clearance rate, c, and the eclipse phase rate of transition, k, had to be fixed to ensure parameter identifiability.…”