Pharmacokinetics of the inactive favipiravir metabolite, favipiravir hydroxide (M1), as a proxy for establishing metabolic activity in patients receiving intravenous favipiravir for treatment of SARS-CoV-2 infection

Background: Favipiravir (FVP) has demonstrated in vitro activity against several RNA viruses, and its use for treatment of high consequence infectious diseases (HCIDs) continues to be evaluated. FVP is primarily metabolized by aldehyde oxidase (AO) to the pharmacologically inactive, favipiravir hydroxide (M1). FVP has complex pharmacokinetics (PK), with auto-inhibition of AO by FVP leading to increased FVP concentrations in plasma over time. Interindividual variability is a hallmark of FVP PK, but the cause of this is undetermined. Here, we report M1 concentrations in plasma from patients hospitalized with COVID-19 enrolled on the AGILE CST-6 clinical trial.

Methods: AGILE CST-6 is a phase I randomized, adaptive study to evaluate safety and efficacy of intravenous (IV) FVP for treatment of COVID-19. Patients with laboratory confirmed COVID-19 were randomized 2:1 to received IV FVP or standard of care (SoC). Four cohorts with six patients were enrolled, with escalating dose per cohort (600, 1200, 1800 and 2400 mg). Patients received IV FVP infusions for 1 h twice daily (BD) for 7 days. Plasma samples were collected on Days 1, 3 and 5 at 0–1 and 6–12 h post-completion of infusion. Extra samples were taken on Days 1 and 3 at pre-dose and 2–4 h post-completion of infusion. FVP and M1 (concentrations) in plasma were determined using validated LC–MS methods and concentrations expressed as ng/mL. PK parameters for M1 and FVP were derived using WinNonlin (Phoenix 64, v8.5). Fixed effect linear modelling of the data was performed using SPSS (IBM, v29.0.1).

Results: A total of 153 samples were evaluable from 16 patients. M1 increased with dose but decreased from Days 1 to 5. Geometric mean (GM) Cmax [M1] were (600|1200|1800|2400 mg) 5873, 9706, 18 576, 25 868 ng/mL on Day 1; 4901, 6808, 10 311 and 12 475 ng/mL on Day 3 and 4275, 7021, 8701 and 15 185 ng/mL on Day 5. (FVP) Cmax were 16 481, 38 006, 52 044, 88 486 ng/mL on Day 1; 16 526, 61 907, 85 362 and 195 067 ng/mL on Day 3; and 23 461, 86 743, 115 781 and 202 676 ng/mL on Day 5. Median (range) M1:FVP ratios were 600 mg: 0.41 (0.06–0.75); 1200 mg: 0.18 (0.01–0.60); 1800 mg: 0.14 (0.05–0.81) and 2400 mg: 0.10 (0.04–0.46) and decreased from Days 1 to 5; M1:FVP ratios were Day 1: 0.42 (0.06–0.81), Day 3: 0.13 (0.01–0.66) and Day 5: 0.10 (0.02–0.48). Interindividual variability was high with %CV > 57%. Dose (94% lower FPV with 600 mg vs. 2400 mg; p < 0.001), M1:FVP ratio (33% decrease in FVP with increasing ratio; p < 0.001) and treatment day (60% decrease in FPV on Day 1 vs. Day 5) were independent, significant predictors of (FVP).

Conclusion: M1 concentrations decrease as FVP plasma concentration increases—both with escalating dose and over treatment duration, indicating potential saturation of metabolic pathways and increased inhibition of AO (due to accumulation of FVP). High interindividual variability in M1:FVP suggests the presence of fast and slow metabolisers. (FVP) was independently predicted by dose, M1:FVP ratio and treatment day, highlighting the complex pharmacokinetic profile of FVP.