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

Abstract

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.

Fig 1. Flowchart of the patients included in the PK analysis of the JIKI trial

Fig 2. Observed trough concentrations of favipiravir at Day-2 (n = 44) and Day-4 (n = 50) after treatment initiation.

Red points represent concentrations measured in patients who died during the trial, green points represent concentrations measured in those who survived. Concentrations obtained in patients receiving adult dose or weighted-based dose are presented in circles and stars, respectively. Lines connect data obtained in the 28 patients who had both measurements at Day-2 and Day-4. Boxplots represent the distribution of the concentrations. The lower and upper hinges correspond to the first and third quartiles. The upper whisker extends from the hinge to the highest value that is within 1.5 * IQR of the hinge, where IQR is the inter-quartile range, or distance between the first and third quartiles. The lower whisker extends from the hinge to the lowest value within 1.5 * IQR of the hinge.

Fig 3. Observed trough concentrations (y-axis) versus predicted trough concentrations (x-axis) at Day-2 (left, n = 44 observations) and Day-4 (right, n = 50) after treatment initiation.

Red points represent concentrations measured in patients who died during the trial, green points represent concentrations measured in those who survived.

Fig 4. Difference in Ct values at Day-2 (left) or Day-4 (right) from baseline (the larger the value the larger the viral decline) versus drug concentrations.

Top: patients with a low baseline Ct value (Ct<20) (n = 15 and 12); bottom: patients with a high baseline Ct value (Ct>=20) (bottom, n = 26 and 37). Red points represent concentrations measured in patients who died during the trial, green points represent concentrations measured in those who survived. Triangles indicate Ct values that were above 40 (detection limit) and were treated as equal to 40, and circles are observed values. Black lines are Loess trend lines.