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
:1. Introduction
2. Materials and Methods
2.1. In Vitro Propagation of FIPV I and II
2.2. Determination of Antiviral Efficacy In Vitro
2.3. Single Dose Pharmacokinetics of Orally Administered MPV, GS-441524, and RDV and Intravenously Administered RDV
2.4. LCMSMS Quantitation of Serum MPV Concentrations and Pharmacokinetic Analysis
2.5. Mass Spectrometry and Liquid Chromatography Conditions
2.6. LC-MS/MS Quantification of GS-441524 in Plasma
2.7. Pharmacokinetic Analysis
3. Results
3.1. All of the Antiviral Agents Effectively Block the In Vitro Replication of Both Serotype I and II FIPV as Monotherapies
3.2. Select Antiviral Agents Have a Synergistic Effect When Used in Combination
3.3. Pharmacokinetics of Oral MPV in Cats
3.4. Pharmacokinetics of GS-441524 after Administration of GS-441524 or RDV in Cats
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cat ID | Cmax (ng/mL; µM) | AUC (h*ng/mL) | Vz/F (L/kg) | Cl/F (L/h/kg) | MRT (h) |
---|---|---|---|---|---|
20-024 | 9.3 (0.03) | 39.6 | 1101.7 | 209.0 | 4.4 |
20-025 | 3.6 (0.01) | 21.7 | 1229.4 | 381.8 | 8.1 |
20-031 | 29.8 (0.09) | 21.4 | 312.4 | 449.6 | 1.2 |
Mean | 14.2 (0.04) | 27.5 | 881.1 | 346.8 | 4.6 |
SD | 13.8 | 10.4 | 405.5 | 101.3 | 3.4 |
Cat ID | Cmax (ng/mL; μM) | Tmax (h) | Kel (1/h) | T1/2 (h) | AUC (h*ng/mL) | MRT (h) |
---|---|---|---|---|---|---|
20-024 | 265 (1.02) | 3.0 | 0.12 | 6 | 1709.47 | 8.33 |
20-025 | 154 (0.15) | 9.0 | 0.29 | 2.4 | 950.03 | 10.51 |
20-031 | 1950 (7.52) | 1.0 | 0.26 | 2.65 | 2679.57 | 2.46 |
Mean | 790 (3.05) | 4.3 | 0.2 | 3.1 | 1779.7 | 7.1 |
SD | 1006 | 4.2 | 0.1 | 1.2 | 866.9 | 4.2 |
Cat ID | Cmax (ng/mL; μM) | Tmax (h) | T1/2 (h) | AUC (h*ng/mL) | F% * |
---|---|---|---|---|---|
20-036 | 13,300 (45.66) | 8 | 4.5 | 132,232 | 235 |
20-044 | 9100 (31.24) | 3 | 8.8 | 54,756 | 100 |
20-046 | 8470 (29.08) | 3 | 5.6 | 82,135 | 145 |
Mean | 10,290 (35.33) | 4.7 | 6.3 | 89,708 | 160 |
SD | 2625 (9.01) | 2.9 | 2.2 | 39,028 | 69 |
Cat ID | Cmax (ng/mL;μM) | Tmax (h) | T1/2 (h) | AUC (h*ng/mL) | F% * |
20-003 | 2100 (7.21) | 8 | 5.9 | 31,747 | 120 |
20-024 | 2390 (8.21) | 8 | 4.6 | 28,252 | 103 |
20-031 | 2950 (10.13) | 6 | 6.0 | 36,116 | 137 |
Mean | 2480 (8.51) | 7.3 | 5.5 | 32,038 | 120 |
SD | 432 (1.48) | 1.2 | 0.8 | 4077 | 17 |
Cat ID | Cmax (ng/mL; μM) | Tmax (h) | T1/2 (h) | AUC (h*ng/mL) |
---|---|---|---|---|
20-045 | 1730 (5.94) | 0.5 | 5.3 | 14,271 |
21-001 | 1960 (6.73) | 1 | 5.7 | 15,291 |
21-004 | 2320 (7.97) | 1 | 4.5 | 9924 |
Mean | 2003 (6.88) | 0.83 | 5.2 | 13,162 |
SD | 297 (1.0) | 0.29 | 0.6 | 2850 |
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Cook, S.; Wittenburg, L.; Yan, V.C.; Theil, J.H.; Castillo, D.; Reagan, K.L.; Williams, S.; Pham, C.-D.; Li, C.; Muller, F.L.; et al. 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. Viruses 2022, 14, 2429. https://doi.org/10.3390/v14112429
Cook S, Wittenburg L, Yan VC, Theil JH, Castillo D, Reagan KL, Williams S, Pham C-D, Li C, Muller FL, et al. 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. Viruses. 2022; 14(11):2429. https://doi.org/10.3390/v14112429
Chicago/Turabian StyleCook, Sarah, Luke Wittenburg, Victoria C. Yan, Jacob H. Theil, Diego Castillo, Krystle L. Reagan, Sonyia Williams, Cong-Dat Pham, Chun Li, Florian L. Muller, and et al. 2022. "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" Viruses 14, no. 11: 2429. https://doi.org/10.3390/v14112429