Favipiravir pharmacokinetics in immunocompromised infants and children with chronic RNA viral infections

ABSTRACT

IntroductionFavipiravir selectively inhibits RNA polymerase responsible for single-stranded viral replication. It is licensed for treating influenza and repurposed to treat other diseases such as Ebola and COVID-19. It is metabolised by hepatic aldehyde oxidase (AO) and is an AO inhibitor with complex pharmacokinetics. We have used favipiravir, in combination with other antivirals, in severely immunocompromised children with life-threatening RNA virus infections. As an unlicensed indication, favipiravir pharmacokinetics were routinely monitored at our institution. Population pharmacokinetic model is used to describe the favipiravir pharmacokinetic properties, drug exposure and sources of variability in these children.MethodsRoutine favipiravir plasma levels of 9 patients (0.8–11yrs, mean age=5.3yrs;median weight=15kg) were analysed retrospectively (62 samples). All patients received favipiravir 200mg or 400mg tds and had at least one plasma level 45min (peak), 3h and 8h (trough) post-dose. Parameter estimation and model simulation properties (visual predictive check) were assessed using R language (v 4.1.2) and RStudio (2022.02.0+443).ResultsA one-compartment model with weight as covariate best describes the data, with (1) elimination clearance=1L/h and volume of distribution=7.54L, both allometric scaled centring at median weight, and (2) estimated t1/2=5.17h with Cmax = 24µg/mL at 200mg and 41µg/mL at 400mg.ConclusionsTo our knowledge this is the first report of favipiravir pharmacokinetic parameters in infants and young children. Weight significantly improves the model fit as a covariate. Reported EC50 for norovirus in vitro was 19–39µg/mL and enterovirus 71 was 23µg/mL, indicating higher favipiravir doses or combination with other antivirals are required.