Response to "Dose Rationale for Favipiravir Use in Patients Infected With SARS-CoV-2".

Dear Editor,

We appreciate the letter by Eloy et al. for their comments and complement regarding our review. , Two independent in vitro studies indicated that favipiravir (T‐705) inhibited severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) replication in Vero E6 cells with half‐maximal effective concentration (EC50) values of 61.88 μM (9.4 μg/mL) and > 100 μM (15.7 μg/mL), respectively. Data from the authors’ group suggests an EC50 value in the range 40–80 µg/mL (X. de Lamballerie & F. Touret, unpublished results). I agree with the authors’ assumption that favipiravir shows similar EC50 against SARS‐CoV‐2 and Ebola virus (EBOV). As favipiravir is a prodrug that requires metabolic activation through ribosylation and phosphorylation in the host cells to form its triphosphate form (favipiravir‐RTP), we think that variation in favipiravir activation by the cultured cells may, at least partially, contribute to the difference in the in vitro EC50 among studies.

Based on the EC50 from an in vitro study, plasma concentrations obtained from the JIKI trial, and simulations from a pharmacokinetic model, the authors suggested a higher favipiravir dose (loading dose of 2,400 mg b.i.d. on day zero, followed by a maintenance dose of 1,600 mg b.i.d. for 9 days) to achieve a pharmacologically relevant target trough concentration of 40–80 µg/mL in coronavirus disease 2019 (COVID‐19). An increase in the maintenance dose definitely increases the overall drug exposure. However, as mentioned above, favipiravir is a prodrug that requires metabolic activation, whereas tissue and cellular exposure of the activate metabolites favipiravir‐RTP is more critical. Self‐inhibition of its metabolism to the formation of T‐705M1 in the liver after continuous use may result in an increase in circulating T‐705/T‐705M1 ratio, and, thus, facilitate the uptake and activation of favipiravir in the tissues. A decrease in trough plasma concentrations of favipiravir does not mean a decreased exposure of the active metabolite favipiravir‐RTP in the tissues. We think that this is an issue that deserves further study and discussion. A randomized clinical trial has evaluated the safety and efficacy of favipiravir in patients with COVID‐19 in China. A dose regimen including 1,600 mg b.i.d. on day 1, followed by 600 mg b.i.d. for 7–10 days from day 2 was adopted in the trial in COVID‐19 patients. The results showed some evidence of efficacy, as indicated by 7 day's clinical recovery rate, time of fever reduction, and cough relief in ordinary patients. It is noteworthy that 31.9% of the patients showed antiviral adverse effects, including increased serum uric acid, abnormal liver function tests, and digestive tract reaction, albeit these adverse effects were mild and manageable. Although the suggested high maintenance dose by Eloy et al. has been practiced in a few EBOV‐infected patients, this high dose should be used with caution in COVID‐19. Close monitoring of the concentrations of the drug, especially for the active metalite favipiravir‐RTP, if possible, and clinically relevant adverse events are suggested when favipiravir is used with a higher dose.

Funding

No funding was received for this work.

Conflict of Interest

The authors declared no competing interests for this work.