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

Posted on by ucnvil0

Background 

Favipiravir selectively inhibits RNA polymerase responsible for single-stranded viral replication. It is licensed for treating influenza and repurposed to treat other diseases such as Ebola1 and COVID-192. It is metabolised by hepatic aldehyde oxidase (AO) and is an AO inhibitor with complex pharmacokinetics. AO expression is shown to rapidly increase in first two years of life and has great inter-individual differences in activity3.  Individual case reports of using favipiravir in children have been published, however, no pharmacokinetic information has been reported in infants and young children. Population pharmacokinetic model allows a population to be described using sparse data and offers a strategy to tackle the lack of prescribing information for children. These mathematical models describe drug pharmacokinetic properties, exposure and sources of variability in the studied population. We have used favipiravir, in combination with other antivirals, in severely immunocompromised children with life-threatening RNA virus infections, including RSV and norovirus. As it is an unlicensed indication, favipiravir pharmacokinetics were routinely monitored at our institution.  

 

Aim 

To describe the pharmacokinetic properties of favipiravir in infants and young children using population pharmacokinetics. 

 

Method 

Routine blood favipiravir plasma levels of 10 patients (mean age = 4 years (0.8-16 years)) were analysed retrospectively (97 samples). All patients received favipiravir 600mg or 1200mg per day in two- to three-divided doses and had at least one plasma level 45 minutes (peak), 3 hours, and 8 hours (trough) post-dose. Parameter estimation and assessment of model simulation properties (visual predictive check) were undertaken using nlmixr2 (v2.0.71) and Rxode (v2.0.7) hosted in R. 

 

Result 

A one-compartment model with weight as covariate best describes the data, with elimination clearance= 3.79 L/h/70kg and volume of distribution=43.51 L/70kg, both allometric scaled centring at median weight, and estimated half-life = 7.43 hours. 

 

Discussion 

We have explored the favipiravir pharmacokinetic parameters in infants and young children. We observe similar predicted pharmacokinetic parameters in children compared to those reported in adults. Weight significantly improves the model fit as a covariate. The introduction of the length of treatment did not improve the model, suggesting clearance will reach an equilibrium after chronic use. Dosing simulations demonstrated that the current regime will not yield the effective plasma concentrations required to achieve viral clearance or viral load reduction for RSV or norovirus, indicating higher doses or combinations with other antivirals are required. This result was used to inform local dosing guidelines. 

Reference

  1. MadelainV, Nguyen TH, Olivo A, De LamballerieX, Guedj J, Taburet AM, Mentré F. Ebola virus infection: review of the pharmacokinetic and pharmacodynamic properties of drugs considered for testing in human efficacy trials. Clinical pharmacokinetics. 2016 Aug;55(8):907-23. 
  2. Yavuz S, Ünal S. Antiviral treatment of COVID-19. Turkish journal of medical sciences. 2020;50(9):611-9.
  3. TayamaY, Miyake K, Sugihara K, Kitamura S, Kobayashi M, Morita S, Ohta S, Kihira K. Developmental changes of aldehyde oxidase activity in young Japanese children. Clinical Pharmacology & Therapeutics. 2007 Apr;81(4):567-72
2023