Dose Rationale for Favipiravir Use in Patients Infected With SARS‐CoV‐2

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Abstract

We read with a great interest the paper by Du and Chen suggesting dosing regimen of favipiravir in coronavirus disease 2019.1 We would like to complement their observations with our pharmacokinetic (PK)/pharmacodynamic experience of favipiravir against Ebola virus (EBOV).2, 3 The drug half-maximal effective concentration (EC50) against EBOV and severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) are 10–60 µg/mL and 9.4 µg/mL,4 respectively. However, results obtained by our working group suggest a higher value of EC50, in the range of 40–80 µg/mL (X. de Lamballerie and F. Touret, unpublished results). We, therefore, use the conservative assumption that the drug EC50 against SARS-CoV-2 is in the same range as against EBOV. The dose used in Ebola infected patients was 6,000 mg on day zero (D0) followed by 1,200 mg b.i.d. for 9 days (JIKI trial). The median trough concentrations of favipiravir at day 2 and day 4 were 46.1 and 25.9 µg/mL, respectively, which was too low to significantly reduce viral load levels.2, 5 Rather, results in nonhuman primates treated with higher doses of favipiravir showed that trough concentrations of 70–80 µg/mL3 could significantly reduce viral replication. Thus, our results show that a dose lower than in the JIKI trial is unlikely to achieve target drug concentrations against SARS-CoV-2. Further, our simulations using a PK model accounting for the nonlinear PKs of favipiravir suggest that a loading dose of 2,400 mg b.i.d. on D0, followed by a maintenance dose of 1,600 mg b.i.d. for 9 days should achieve trough concentrations close to 70 µg/mL, and may be more relevant pharmacologically. Of note, this loading dose has already been used in Ebola infected patients from (i) the FORCE study (NCT02739477), in which two patients received a loading dose of 2,400 mg b.i.d. on D0 and a maintenance dose of 1,800 mg b.i.d. for 13 days and (ii) a MEURI protocol, in which two patients received a maintenance dose of 2,400 mg b.i.d. for 10–15 days. Given the lack of data on drug PKs and safety at these doses, we recommend to have a close cardiac and daily hepatic monitoring during the treatment period along with a regular monitoring of favipiravir concentration. A corrected QT > 500 ms, delta corrected QT > 60 ms or prolongation of PR or QRS should lead to treatment discontinuation. As pointed out by Du and Chen, favipiravir plasma exposure may be larger in Asian populations, and therefore, we suggest particular caution when using high dose of favipiravir in these populations. No funding was received for this work. All authors declared no conflict of interest.

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