Favipiravir pharmacokinetics in Ebola-Infected patients of the JIKI trial reveals concentrations lower than targeted

PLoS Negl Trop Dis. 2017 Feb 23;11(2):e0005389. doi: 10.1371/journal.pntd.0005389. eCollection 2017 Feb.


Background: In 2014-2015, we assessed favipiravir tolerance and efficacy in patients with Ebola virus (EBOV) disease (EVD) in Guinea (JIKI trial). Because the drug had never been used before for this indication and that high concentrations of the drugs were needed to achieve antiviral efficacy against EBOV, a pharmacokinetic model had been used to propose relevant dosing regimen. Here we report the favipiravir plasma concentrations that were achieved in participants in the JIKI trial and put them in perspective with the model-based targeted concentrations.

Methods and findings: Pre-dose drug concentrations were collected at Day-2 and Day-4 of treatment in 66 patients of the JIKI trial and compared to those predicted by the model taking into account patient's individual characteristics. At Day-2, the observed concentrations were slightly lower than the model predictions adjusted for patient's characteristics (median value of 46.1 versus 54.3 μg/mL for observed and predicted concentrations, respectively, p = 0.012). However, the concentrations dropped at Day-4, which was not anticipated by the model (median values of 25.9 and 64.4 μg/mL for observed and predicted concentrations, respectively, p<10-6). There was no significant relationship between favipiravir concentrations and EBOV viral kinetics or mortality.

Conclusions: Favipiravir plasma concentrations in the JIKI trial failed to achieve the target exposure defined before the trial. Furthermore, the drug concentration experienced an unanticipated drop between Day-2 and Day-4. The origin of this drop could be due to severe sepsis conditions and/or to intrinsic properties of favipiravir metabolism. Dose-ranging studies should be performed in healthy volunteers to assess the concentrations and the tolerance that could be achieved with high doses.

Trial registration: ClinicalTrials.gov NCT02329054.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Amides / administration & dosage
  • Amides / pharmacokinetics*
  • Antiviral Agents / administration & dosage
  • Antiviral Agents / pharmacokinetics*
  • Child
  • Child, Preschool
  • Ebolavirus / drug effects
  • Ebolavirus / physiology
  • Female
  • Guinea
  • Hemorrhagic Fever, Ebola / drug therapy*
  • Hemorrhagic Fever, Ebola / virology
  • Humans
  • Male
  • Middle Aged
  • Pyrazines / administration & dosage
  • Pyrazines / pharmacokinetics*
  • Young Adult


  • Amides
  • Antiviral Agents
  • Pyrazines
  • favipiravir

Associated data

  • ClinicalTrials.gov/NCT02329054

Grants and funding

The JIKI trial was supported by grants from the French National Agency for AIDS and viral hepatitis research (ANRS, Paris, France, http://www.anrs.fr/), the French Institute for Health Research (Inserm, Paris, France, http://www.inserm.fr/) and the European Commission (EU Horizon 2020 programme, grant N° 666092 - REACTION, http://ec.europa.eu/programmes/horizon2020/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.