Favipiravir pharmacokinetics in saliva, tears and nasal secretions of hospitalized COVID-19 patients following intravenous favipiravir administration

Abstract

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Favipiravir pharmacokinetics in saliva, tears and nasal secretions of hospitalized COVID-19 patients following intravenous favipiravir administration

Elizabeth Challenger¹, Tim Rowland^2,3, Laura Else¹, Laura Dickinson¹, Colin Hale², Rebecca Lyon², Henry Pertinez⁴, Andrew Owen⁴, Helen Reynolds¹, Justin Chiong¹, Richard FitzGerald¹, Saye Khoo¹ and Tom Fletcher³

¹Centre for Experimental Therapeutics, University Of Liverpool; ²Liverpool University Hospitals NHS Foundation Trust; ³Liverpool School of Tropical Medicine; ⁴Centre of Excellence for Long Acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, Institute of Integrative, Systems and Molecular Biology, University of Liverpool

Background: SARS-CoV-2 is transmitted between individuals when virions trapped in aerosols or large droplets are expelled through conversation, coughing or sneezing. Due to consistent emergence of new variants, evaluation of therapeutics for SARS-CoV-2 is crucial to maximize treatment options should more virulent or treatment resistant strains arise. Establishing the concentration of potential therapeutics in sites of SARS-CoV-2 transmission is essential to assess compartmentalization and prophylactic potential. Here we report favipiravir (FVP) concentrations in saliva, tears and nasal secretions in hospitalized COVID-19 patients enrolled on the AGILE CST-6 clinical trial.

Materials and methods: AGILE CST-6 is a randomized, multicentre, seamless, adaptive, phase I/II platform study to evaluate safety and efficacy of intravenous (IV) FVP for the treatment of COVID-19. Patients with laboratory confirmed COVID-19 were enrolled 2:1 to receive IV FVP or standard of care (SoC); four cohorts of six patients (n = 4 FVP, n = 2 SoC) were enrolled, with escalating doses per cohort (600 mg, 1200 mg, 1800 mg, 2400 mg). Patients received IV FVP twice daily over 7 days, with paired plasma and non-plasma samples (saliva, nasal swabs, tear strips) collected between 6 and 12 h post-completion of IV infusion on days 1 and 3. FVP was quantified using validated LC-MS methods and FVP concentrations expressed as ng/mL. Descriptive statistics were computed (Phoenix 64, WinNonlin, v8.3) and FVP non-plasma:plasma ratios (NP:P) determined. Relationships between paired quantifiable non-plasma and plasma concentrations were evaluated by linear regression.

Results: Sixteen individuals [seven females at birth; median (range) age, weight, number of days with COVID-19 symptoms were 76.5 years (52–93), 78.6 kg (52.1–125) and 5 days (2–11), respectively] received at least six doses of IV FVP. Analysis included 32 plasma/nasal, 31 saliva and 30 tear samples. FVP was quantifiable in 100%/91%/97% of saliva/nasal/tear samples collected 6.1–7.2 h post IV infusion. FVP concentrations increased with dose [600|1200|1800|2400 mg bd] although significant intra- and inter-subject variability was noted within the dosing cohorts. On day 3, median FVP concentrations were 1336/38 730/47 000/125 468 ng/mL in plasma, 69/1042/4218/9742 ng/mL in saliva, 2455/2247/7968/13 420 ng/mL in nasal secretions and 693/5762/3620/34 985 ng/mL in tears, respectively. Accumulation of FVP was observed in all matrices from day 1 to day 3. Median (range) NP:P ratios were saliva 0.06 (0.01–0.28), nasal 0.42 (0.03–21.28) and tears 0.30 (0.00–6.54).

Non-plasma and plasma concentrations were significantly correlated on day 3 (r > 0.724; p < .003). On day 1, 13% of plasma samples (all 2400 mg dose) were above the FVP SARS-CoV-2 in vitro EC90 (24.9 μg/mL); all non-plasma levels were below this threshold. At day 3, 56% of plasma samples (≥1200 mg dose), 12% of nasal and 6% of tear samples (2400 mg dose) exceeded this threshold.

Conclusions: This is the first report of FVP measured at sites of SARS-CoV-2 transmission. These data suggest that achieving concentrations equivalent to the EC90 may be difficult to achieve in saliva, nasal and ocular compartments, even when administering higher dose IV FVP (2400 mg bd). FVP predominantly penetrates into nasal secretions, followed by tears and saliva, with substantial interindividual variability. PK/PD relationships for IV FVP are under evaluation.