Philippine Eloy

We read with a great interest the paper by Du et Chen suggesting dosing regimen of favipiravir in COVID‐19¹. We would like to complement their observations with our PK/PD experience of favipiravir against Ebola virus (EBOV). The drug EC₅₀ against EBOV and SARS‐CoV‐2 are 10‐60 µg/ml and 9.4 µg/ml⁴, respectively. However results obtained by our working group suggest a higher value of EC₅₀, in the range 40‐80 µg/ml (X. de Lamballerie & F. Touret, unpublished results).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.

Amikacin infusion requires targeting a peak serum concentration (C_max) 8–10 times the minimal inhibitory concentration, corresponding to a C_max of 60–80 mg/L for the least susceptible bacteria to theoretically prevent therapeutic failure. Because drug pharmacokinetics on extracorporeal membrane oxygenation (ECMO) are challenging, we undertook this study to assess the frequency of insufficient amikacin C_max in critically ill patients on ECMO and to identify relative risk factors. This was a prospective, observational, monocentric study in a university hospital. Patients on ECMO who received an amikacin loading dose for suspected Gram-negative infections were included. The amikacin loading dose of 25 mg/kg total body weight was administered intravenously and C_max was measured 30 min after the end of the infusion. Independent predicators of C_max < 60 mg/L after the first amikacin infusion were identified with mixed-model multivariable analyses. Various dosing simulations were performed to assess the probability of reaching 60 mg/L < C_max < 80 mg/L. A total of 106 patients on venoarterial ECMO (VA-ECMO) (68%) or venovenous-ECMO (32%) were included. At inclusion, their median (1st; 3rd quartile) Sequential Organ-Failure Assessment score was 15 (12; 18) and 54 patients (51%) were on renal replacement therapy. Overall ICU mortality was 54%. C_max was < 60 mg/L in 41 patients (39%). Independent risk factors for amikacin under-dosing were body mass index (BMI) < 22 kg/m² and a positive 24-h fluid balance. Using dosing simulation, increasing the amikacin dosing regimen to 30 mg/kg and 35 mg/kg of body weight when the 24-h fluid balance is positive and the BMI is ≥ 22 kg/m² or < 22 kg/m² (Table 3), respectively, would have potentially led to the therapeutic target being reached in 42% of patients while reducing under-dosing to 23% of patients. ECMO-treated patients were under-dosed for amikacin in one third of cases. Increasing the dose to 35 mg/kg of body weight in low-BMI patients and those with positive 24-h fluid balance on ECMO to reach adequate targeted concentrations should be investigated.