An Optimized Bioassay for Screening Combined Anticoronaviral Compounds for Efficacy against Feline Infectious Peritonitis Virus with Pharmacokinetic Analyses of GS-441524, Remdesivir, and Molnupiravir in Cats

Abstract

Feline infectious peritonitis (FIP) is a fatal disease of cats that currently lacks licensed and affordable vaccines or antiviral therapeutics. The disease has a spectrum of clinical presentations including an effusive (“wet”) form and non-effusive (“dry”) form, both of which may be complicated by neurologic or ocular involvement. The feline coronavirus (FCoV) biotype, termed feline infectious peritonitis virus (FIPV), is the etiologic agent of FIP. The objective of this study was to determine and compare the in vitro antiviral efficacies of the viral protease inhibitors GC376 and nirmatrelvir and the nucleoside analogs remdesivir (RDV), GS-441524, molnupiravir (MPV; EIDD-2801), and β-D-N4-hydroxycytidine (NHC; EIDD-1931). These antiviral agents were functionally evaluated using an optimized in vitro bioassay system. Antivirals were assessed as monotherapies against FIPV serotypes I and II and as combined anticoronaviral therapies (CACT) against FIPV serotype II, which provided evidence for synergy for selected combinations. We also determined the pharmacokinetic properties of MPV, GS-441524, and RDV after oral administration to cats in vivo as well as after intravenous administration of RDV. We established that orally administered MPV at 10 mg/kg, GS-441524 and RDV at 25 mg/kg, and intravenously administered RDV at 7 mg/kg achieves plasma levels greater than the established corresponding EC50 values, which are sustained over 24 h for GS-441514 and RDV.

Thirty‐two cats with effusive or non‐effusive feline infectious peritonitis treated with a combination of remdesivir and GS‐441524

“…No studies have yet assessed optimal dosing of remdesivir, the prodrug of GS‐441524, for the treatment of FIP in cats. Doses of remdesivir in our study therefore were extrapolated from dosages used in human medicine, from previous studies on GS‐441524 and from anecdotal evidence 2,7‐9,14,17 . Optimal dosing of PO GS‐441524 also has not yet been established although dosages of 5 to 10 mg/kg for 12 weeks have been used successfully 9,16 .…”

“…Doses of remdesivir in our study therefore were extrapolated from dosages used in human medicine, from previous studies on GS-441524 and from anecdotal evidence. 2,[7][8][9]14,17 Optimal dosing of PO GS-441524 also has not yet been established although dosages of 5 to 10 mg/kg for 12 weeks have been used successfully. 9,16 Doses equivalent to the doses used for IV remdesivir were used in our study because of the poor oral bioavailability of GS-441524 identified in other species despite its molecular weight being roughly half that of remdesivir.…”

“…Similarly, dose recommendations for remdesivir and PO GS-441524 so far have been based on in vitro studies, experimental and limited field studies using injectable GS-441524 and anecdotal evidence. 2,[6][7][8][9]13,14 Little therefore is known about optimal treatment doses for different disease presentations, treatment length and adverse effects with injectable remdesivir and PO GS-441524.…”

Outcomes of treatment of cats with feline infectious peritonitis using parenterally administered remdesivir, with or without transition to orally administered GS‐441524

“…This might support a clinical decision to emphasize monitoring physical examination findings in the first half of treatment and hematologic and biochemical measurements in the latter half of treatment. Critically, the presence of hyperglobulinemia beyond the first 6 weeks of treatment should prompt a dosage increase, or consideration of the addition of a second antiviral agent (such as the protease inhibitor GC376 23 or molnupiravir [24][25][26] 27 Increase in serum ALT activity often resolved during treatment, or in some instances persisted beyond the point where treatment was discontinued (without FIP relapse), and therefore is unlikely to represent an adverse drug effect.…”

Dual combined antiviral treatment with remdesivir and nirmatrelvir/ritonavir in patients with impaired humoral immunity and persistent SARS‐CoV‐2 infection

“…Patients urgently needing to resume the treatment of their original comorbidity were favored. Our decision was primarily motivated by the potential synergistic effect of two antiviral drugs with different biological targets 23,24 and by the minimal residual activity of MoAB related to the increasing prevalence of omicron subvariant BA.5 and BQ.1.1. 11,12 Nirmatrelvir, a novel inhibitor of the SARS-CoV-2 main protease, has been authorized by the United States Food and Drug Administration (FDA) in combination with ritonavir, a strong CYP3A inhibitor, for emergency use since December 2021 for the treatment of mild-to-moderate COVID-19 in adults who are at high risk for progression to severe COVID-19.…”