Pharmacokinetics of Orally Administered GS-441524 in Dogs

Abstract

Despite being FDA-approved for COVID-19, the clinical efficacy of remdesivir (Veklury^®) remains contentious. We previously pointed out pharmacokinetic, pharmacodynamic and toxicology reasons for why its parent nucleoside GS-441524, is better suited for COVID-19 treatment. Here, we assess the oral bioavailability of GS-441524 in beagle dogs and show that plasma concentrations ~24-fold higher than the EC₅₀ against SARS-CoV-2 are easily and safely sustained. These data support translation of GS-441524 as an oral agent for COVID-19.

Figure 1.. Plasma concentrations of GS-441524 following a single oral dose of 214 remdesivir or GS-441524 in dogs.

(A) Head-to-head PK comparison following a single 215 equimolar dose of remdesivir (black, 13.6 mg/kg) and GS-441524 (orange, 6.5 mg/kg) 216 in male beagle dogs (N=1 per compound). Both compounds were administered in 217 capsule form. Plasma concentrations of GS-441524 following compound administration 218 are plotted for the following timepoints (h): 0.5, 1, 3, 6, 8, 24. A focused view of GS219 441524 concentrations following oral administration of remdesivir is shown on the left. 220 Dashed red line corresponds to the levels of GS-443902 (NTP) formed in whole blood following oral administration of GS-441524 as quantified u sing a highly sensitive dried blood spot assay. Oral administration of RDV did not produce detectable levels of GS-443902 in whole blood. (B) Comparison of plasma concentrations of GS-441524 following oral administration as a solution (black, 5 mg/kg; N=3) or as a capsule (orange, 6.5 mg/kg; N=1). (C) Mean PK parameters following various routes of administration of GS-441524 and RDV. Raw values for GS-441524 dosed IV and PO dosed as a solution are adapted from NCATS OpenData Portal and have been re-calculated to match the sampling timeframe of the capsule studies (T=0.5–24 h). All PK parameters were calculated using PKSolver 2.0. In panels A and B, dotted lines correspond to EC₅₀ (bottom) and EC₉₀ (top) values reported for GS-441524 in SARS-CoV-2-infected Calu3 cells (19).