Favipiravir tissue distribution and inhibitory quotients in preclinical models: towards a pipeline for evidence-based antiviral repurposing.

OBJECTIVES

Favipiravir (T-705) shows potent in vitro activity but inconsistent in vivo efficacy. We assessed how plasma exposure and tissue distribution shape antiviral coverage using a tissue-based PK/PD framework.

METHODS

Favipiravir and its hydroxylated metabolite (M1) were quantified in plasma and multiple organs of Syrian golden hamsters after single and repeated dosing and compared with a non-human primate dataset. We derived tissue penetration factors (TPFs), metabolic ratios (MR) and inhibitory quotients (IQ) against published EC50 values for representative RNA viruses and integrated these results with available human pharmacokinetic data.

RESULTS

Favipiravir absorbed rapidly and distributed heterogeneously, reaching highest levels in kidney, gut and respiratory organs with limited brain access; M1 was enriched in liver and kidney. Organ exposure ranking was broadly similar across species. Tissue IQs were often lower than plasma IQs, indicating that plasma monitoring can overestimate target-organ coverage. IQ analysis suggested favourable coverage for influenza and RSV, heterogeneous, dose-dependent coverage for chikungunya, Rift Valley fever viruses and Orthohantavirus andesense (ANDV), intermediate coverage for Zika virus, and limited coverage for SARS-CoV-2, ebolavirus and West Nile virus. For some viruses, coverage may require higher exposures, prompting dose reassessment and safety data. The IQ patterns aligned with reported preclinical efficacy, and human pharmacokinetics suggested robust exposure margins for influenza but insufficient margins for SARS-CoV-2 and ebolavirus.

CONCLUSIONS

Tissue-based IQs refine the interpretation of exposure-response relationships and help explain favipiravir's variable in vivo performance. The same framework can be refined and applied to other antiviral candidates to support preparedness strategies.