Assessing Stability of Remdesivir (GS-5734) and Conversion to GS-441524 in Feline Plasma and Whole Blood

Overview

Journal Vet Q

Specialty Veterinary Medicine

Date 2024 Jan 30

PMID 38288972

Authors

Sally J Coggins

Benjamin Kimble

Richard Malik

Mary F Thompson

Jacqueline M Norris

Merran Govendir

Affiliations

Soon will be listed here.

Abstract

Feline infectious peritonitis (FIP) is a potentially fatal coronavirus-driven disease of cats. Treatment with nucleoside analogue GS-441524 and or prodrug remdesivir (RDV) have produced remission in both experimentally induced and naturally occurring FIP, yet information regarding metabolism of RDV into GS-441524 in cats is scarce. This study assessed possible phase I metabolism of RDV in cats, utilising an feline microsome model with in vitro t and Cl calculated using the substrate depletion method. A previously validated high-performance liquid chromatography (HPLC) fluorescence method was utilised for detection and analysis of RDV and GS-441524. Qualitative yield of RDV and intermediate metabolite GS-441524 were determined following microsome incubation, then compared to whole blood and plasma incubations. microsome incubation resulted in rapid depletion of RDV, though it did not appear to resemble a conventional phase I-dependent reaction in cats, as it is in humans and dogs. Depletion of RDV into GS-441524 was demonstrated in whole blood , suggesting cats convert RDV to GS-441524, likely via blood esterases, as observed in mice and rats. RDV metabolism is unlikely to be impacted by impaired liver function in cats. Furthermore, as RDV depletes within minutes, whereas GS-441524 is very stable, whole blood or plasma GS-441524 concentrations, rather than plasma RDV concentrations, are more appropriate for therapeutic drug monitoring (TDM) in cats receiving RDV.

References

Jones S, Novicoff W, Nadeau J, Evans S . Unlicensed GS-441524-Like Antiviral Therapy Can Be Effective for at-Home Treatment of Feline Infectious Peritonitis. Animals (Basel). 2021; 11(8). PMC: 8388366. DOI: 10.3390/ani11082257. View

Rudakova E, Boltneva N, Makhaeva G . Comparative analysis of esterase activities of human, mouse, and rat blood. Bull Exp Biol Med. 2012; 152(1):73-5. DOI: 10.1007/s10517-011-1457-y. View

Deb S, Reeves A, Hopefl R, Bejusca R . ADME and Pharmacokinetic Properties of Remdesivir: Its Drug Interaction Potential. Pharmaceuticals (Basel). 2021; 14(7). PMC: 8308800. DOI: 10.3390/ph14070655. View

Avataneo V, De Nicolo A, Cusato J, Antonucci M, Manca A, Palermiti A . Development and validation of a UHPLC-MS/MS method for quantification of the prodrug remdesivir and its metabolite GS-441524: a tool for clinical pharmacokinetics of SARS-CoV-2/COVID-19 and Ebola virus disease. J Antimicrob Chemother. 2020; 75(7):1772-1777. PMC: 7197584. DOI: 10.1093/jac/dkaa152. View

Obach R, BAXTER J, Liston T, Silber B, Jones B, Macintyre F . The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data. J Pharmacol Exp Ther. 1997; 283(1):46-58. View

Eastman R, Roth J, Brimacombe K, Simeonov A, Shen M, Patnaik S . Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19. ACS Cent Sci. 2020; 6(5):672-683. PMC: 7202249. DOI: 10.1021/acscentsci.0c00489. View

Kimble B, Coggins S, Norris J, Thompson M, Govendir M . Quantification of GS-441524 concentration in feline plasma using high performance liquid chromatography with fluorescence detection. Vet Q. 2023; 43(1):1-9. PMC: 10438854. DOI: 10.1080/01652176.2023.2246553. View

Hu W, Chang L, Yang Y, Wang X, Xie Y, Shen J . Pharmacokinetics and tissue distribution of remdesivir and its metabolites nucleotide monophosphate, nucleotide triphosphate, and nucleoside in mice. Acta Pharmacol Sin. 2020; 42(7):1195-1200. PMC: 7548405. DOI: 10.1038/s41401-020-00537-9. View

Seley-Radtke K, Yates M . The evolution of nucleoside analogue antivirals: A review for chemists and non-chemists. Part 1: Early structural modifications to the nucleoside scaffold. Antiviral Res. 2018; 154:66-86. PMC: 6396324. DOI: 10.1016/j.antiviral.2018.04.004. View

10.

Green J, Syme H, Tayler S . Thirty-two cats with effusive or non-effusive feline infectious peritonitis treated with a combination of remdesivir and GS-441524. J Vet Intern Med. 2023; 37(5):1784-1793. PMC: 10472986. DOI: 10.1111/jvim.16804. View

11.

Tempestilli M, Caputi P, Avataneo V, Notari S, Forini O, Scorzolini L . Pharmacokinetics of remdesivir and GS-441524 in two critically ill patients who recovered from COVID-19. J Antimicrob Chemother. 2020; 75(10):2977-2980. PMC: 7337789. DOI: 10.1093/jac/dkaa239. View

12.

De Clercq E . Antivirals and antiviral strategies. Nat Rev Microbiol. 2004; 2(9):704-20. PMC: 7097272. DOI: 10.1038/nrmicro975. View

13.

Warren T, Jordan R, Lo M, Ray A, Mackman R, Soloveva V . Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016; 531(7594):381-5. PMC: 5551389. DOI: 10.1038/nature17180. View

14.

Jordheim L, Durantel D, Zoulim F, Dumontet C . Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases. Nat Rev Drug Discov. 2013; 12(6):447-64. DOI: 10.1038/nrd4010. View

15.

Hartmann K, Ritz S . Treatment of cats with feline infectious peritonitis. Vet Immunol Immunopathol. 2008; 123(1-2):172-5. PMC: 7132371. DOI: 10.1016/j.vetimm.2008.01.026. View

16.

Barlough J, Shacklett B . Antiviral studies of feline infectious peritonitis virus in vitro. Vet Rec. 1994; 135(8):177-9. DOI: 10.1136/vr.135.8.177. View

17.

Balzarini J, Keyaerts E, Vijgen L, Vandermeer F, Stevens M, De Clercq E . Pyridine N-oxide derivatives are inhibitory to the human SARS and feline infectious peritonitis coronavirus in cell culture. J Antimicrob Chemother. 2006; 57(3):472-81. PMC: 7110042. DOI: 10.1093/jac/dki481. View

18.

Tempestilli M, Stazi G, Maffongelli G, Marini M, Bartoli T, Ippolito G . Plasma concentrations of remdesivir metabolite in a critical COVID-19 patient needing continuous venovenous haemodialysis. Eur J Clin Pharmacol. 2021; 77(10):1583-1585. PMC: 8116063. DOI: 10.1007/s00228-021-03128-7. View

19.

Gordon C, Tchesnokov E, Woolner E, Perry J, Feng J, Porter D . Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. J Biol Chem. 2020; 295(20):6785-6797. PMC: 7242698. DOI: 10.1074/jbc.RA120.013679. View

20.

Williamson B, Feldmann F, Schwarz B, Meade-White K, Porter D, Schulz J . Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Nature. 2020; 585(7824):273-276. PMC: 7486271. DOI: 10.1038/s41586-020-2423-5. View