Zika virus (ZIKV) infection is associated with serious, long-term neurological manifestations. There are currently no approved therapies for the treatment or prevention of ZIKV. Favipiravir (FAV) is a viral polymerase inhibitor with broad-spectrum activity. Our prior studies used static FAV concentrations and demonstrated promising activity. However, the anti-ZIKV activity of dynamic FAV concentrations has never been evaluated in a human cell line. Here we employed the hollow fiber infection model (HFIM) to simulate human pharmacokinetic (PK) profiles associated with clinically-utilized influenza and Ebola FAV dosage regimens and assess the viral burden profiles. Clinically achievable FAV concentrations inhibited ZIKV replication in HUH-7 cells in a dose-dependent fashion (EC50 = 236.5 uM). The viral burden profiles under dynamic FAV concentrations were predicted by mechanism-based mathematical modeling (MBM) and subsequently successfully validated in the HFIM. This validated, translational MBM can now be used to predict the anti-ZIKV activity for other FAV dosage regimens in presence of between patient variability in pharmacokinetics. This approach can be extended to rationally optimize FAV combination dosage regimens which hold promise to treat ZIKV infections in non-pregnant patients.
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