Exploring human drug for feline coronavirus

thodonal / stock.adobe.com

Feline “coronavirus” refers to a single virus species but either of 2 pathotypes, distinguished by their individual paths of destruction.¹ Feline enteric coronavirus, highly contagious via fecal-oral transmission, is usually asymptomatic but can cause mild diarrhea. Feline infectious peritonitis (FIP), on the other hand, is immune mediated and usually fatal.

The effusive (wet) form of FIP typically causes death days to weeks after onset of clinical signs. The noneffusive (dry) form usually kills in weeks to months.² There are occasional survivors,³ despite limited treatment options.

Feline calicivirus, a common cause of upper respiratory tract disease and oral ulceration in cats, can occur in highly virulent forms that have recently kicked off outbreaks of often fatal systemic disease.⁴ Like FIP, feline calicivirus has outrun attempts to harness it with antivirals.

The promise of mefloquine?

These therapeutic voids underscore the need to investigate whether the 2 viruses fall under the treatment umbrella of other types of existing antimicrobials. The human antimalaria drug mefloquine was shown to suppress viral load of feline coronavirus in infected feline kidney cells in vitro, without cytotoxic effects.⁵

Previous studies evaluating the hepatic clearance of mefloquine in cats found no evidence of delayed elimination. Plasma protein binding, they found, is about 99% in both healthy and FIP-infected cats.⁶ Pharmacokinetic data on mefloquine is available for human adults and infants, as well as dogs,⁷ but little information is available for cats.

To assess the antiviral potential of mefloquine in cats, its pharmacokinetic profile is prerequisite for developing a dosage plan. Researchers at the University of Sydney School of Veterinary Science investigated the pharmacokinetics of mefloquine in clinically healthy cats dosed at 62.5 mg twice weekly, for a total of 4 doses. The recently published study⁸ also documented changes in hematologic, biochemical, and physiologic parameters.

Measuring mefloquine in the blood

Seven healthy adult cats, ranging in age from 3 to 7 years with an average weight of 5.4 kg, were recruited from an animal research facility. Cats were housed individually and dosed orally with mefloquine 62.5 mg (one-quarter of a 250-mg tablet) on days 0, 4 (96 hours), 7 (168 hours), and 10 (240 hours). The first dose was administered without food; subsequent doses were given with food. The cats were monitored for adverse reactions for 2 hours after dosing and then observed for 14 days.

To determine mefloquine plasma concentrations, the investigators collected serial blood samples into lithium heparin tubes from anesthetized cats at 0 (pretreatment), 1, 2, 4, 8, 12, 24, 48, 96, 168, 240, and 336 hours after drug administration. On mefloquine administration days 4, 7, and 10, blood samples were collected prior to dosing.

Mefloquine concentrations were measured by high-pressure liquid chromatography. Several data points were calculated, including peak plasma concentration (Cmax), time to reach Cmax (Tmax), elimination half-life, apparent volume of distribution, and apparent clearance.

Two cats were excluded from statistical analysis due to vomiting, and a third was excluded because of outlier results. Hematology and serum biochemistry values were obtained for 6 cats at 0 (pretreatment), 168, and 336 hours.

Once in the body…

The first dose of mefloquine produced an average Cmax of 2.71 µg/ml at 15 hours (Tmax). Spikes in mefloquine plasma concentrations occurred at 168, 240, and 336 hours. The overall highest plasma concentrations (4.06 µg) occurred at 240 hours. The apparent mean volume of distribution was found to be 17.4 L/kg, the apparent systemic clearance was 0.060 L/hr.kg (0-96 hours), and the elimination half-life—based on 24- to 96-hour time points—was 9.3 days (224 hours).

Hematology results were unremarkable for all 6 cats evaluated. Serum biochemistry data showed mild increases in serum symmetric dimethylarginine (SDMA) at 168 and 336 hours, but creatinine concentrations did not rise significantly. Three cats had elevated liver parameters pretreatment, which in 1 cat continued to rise during the study.

Although 2 cats vomited on the first administration of mefloquine, 1 was able to continue the study by being dosed with food.All other cats tolerated the medication well, as the last 3 doses were administered with food.

Antimalarials as antivirals

The only reported use of mefloquine in animals is as an anti-malarial for raptors and penguins.⁹ In vitro, however, antiviral activity has been demonstrated against feline coronavirus,⁵ feline calicivirus,¹⁰ pangolin coronavirus,¹¹ and—in people—dengue type 2 and Zika viruses.¹²

The oral bioavailability of mefloquine in dogs was found to average 78%,7 and peak plasma concentrations in humans were reached at a mean of 17.6 hours.¹³ The current study found a Tmax of 15 hours, comparable to that in people. Also similar in people¹⁴ and the study cats was the apparent mean volume of distribution (17.4 and 19.2 L/kg in cats and humans, respectively). The apparent systemic clearance was more brisk in cats (0.060 L/h/kg) than in people (0.026 L/h/kg), and the corresponding elimination half-life sooner, at 9.3 days in cats vs 20 days in humans.

Food may enhance oral absorption of mefloquine, as mean plasma concentration was higher when the drug administered with food (4.06 µg/ml) than without (2.71 µg/ml). This difference could also be at least partly explained by the cumulative effect of multiple dosings that had occurred prior to the higher reading.

Given that previous research has shown inhibition of both feline coronavirus biotypes when mefloquine is dosed at 10 µM (Cmax, 3.78 µg/ml),⁵ the Cmax peak of 2.71 µg/ml reached in the current study following the initial dose of about 12.5 mg/kg suggests that either dosing with food or using a higher dose might better achieve the desired inhibitory effect.

Other antimalarials also show potential for treating feline coronavirus. Chloroquine has shown inhibitory effect against FIP virus replication, as well as anti-inflammatory potencyin vitro.¹⁵ It also improved clinical signs in cats experimentally infected with FIP, although it increased their serum alanine aminotransferase (ALT). While mefloquine did not increase ALT levels this study, its potency against cats with FIP remains to be seen.

Mefloquine’s other cousin, hydroxychloroquine, which has been investigated for treating people with SARS-CoV-2 (the virus that causes coronavirus disease 2019),¹⁶ has shown in vitro antiviral activity against FIP virus when used with recombinant feline interferon-⍵.¹⁷

Addressing the gaps

The main limitations of this study were the small number of cats included and the short duration for which they were observed for adverse effects. Also, only healthy cats were used, but mefloquine pharmacokinetics may differ between healthy and FIP-infected cats due to the preponderance of acute phase proteins in the latter.

Another limitation was the blood collection protocol used. Anesthetic drugs were given prior to blood collections. It is not possible to separate out their potential contribution to rising SDMA levels, which can signal early kidney compromise, from possible renal impacts of mefloquine.

Hepatic effects were also a little unclear, as 3 of the cats had elevated liver enzymes before treatment. Nevertheless, no significant increases in liver enzymes occurred following mefloquine administration.

Despite these constraints, this study establishes preliminary data for the pharmacokinetic profile of mefloquine in cats and serves as a springboard for planning clinical trials of mefloquine in those with feline coronavirus and calicivirus.

Dr. Capuzzi is a small animal veterinarian and journalist based in the Philadelphia area.

References

1. Felten S, Hartmann K. Diagnosis of feline infectious peritonitis: a review of the current literature. Viruses. 2019;11(11):1068. doi:10.3390/v11111068.
2. Addie D, Belak S, Boucraut-Baralon C, et al. Feline infectious peritonitis. ABCD guidelines on prevention and management. J Feline Med Surg. 2009;11(7):594-604. doi:10.1016/j.jfms.2009.05.008
3. Hugo TB, Heading KL. Prolonged survival of a cat diagnosed with feline infectious peritonitis by immunohistochemistry. Can Vet J. 2015;56(1):53-58.
4. Radford AD, Addie D, Belak S, et al. ABCD guidelines on prevention and management. J Feline Med Surg. 2009;11(7):556-564. doi:10.1016/j.jfms.2009.05.004
5. McDonagh P, Sheehy PA, Norris JM. Identification and characterisation of small molecule inhibitors of feline coronavirus replication. Vet Microbiol. 2014;174(3-4):438-447. doi:10.1016/j.vetmic.2014.10.030.
6. Izes AM. Comparative studies of in vitrohepatic metabolism of mefloquine by feline microsomes and those of other selected species. PhD thesis. Camperdown, NSW, Australia: University of Sydney; November 2019.
7. Schwartz DE, Weber W, Richard-Lenoble D, Gentilini M. Kinetic studies of mefloquine and of one of its metabolites, Ro 21-5104, in the dog and in man. Acta Trop. 1980;37(3):238-242.
8. Yu J, Kimble B, Norris JM, Govendir M. Pharmacokinetic profile of oral administration of mefloquine to clinically normal cats: a preliminary in-vivo study of a potential treatment for feline infectious peritonitis. Animals. 2020;10(6):1000. doi:10.3390/ani10061000
9. Remple JD. Intracellular hematozoa of raptors: a review and update. J Avian Med Surg. 2004;18(2):75-88. doi:10.1647/2003-008
10. McDonagh P, Sheehy PA, Fawcett A, Norris JM. Antiviral effect of mefloquine on feline calicivirus in vitro. Vet Microbiol. 2015;176(3-4):370-377. doi: 10.1016/j.vetmic.2015.02.007
11. Fan HH, Wang LQ, Liu WL, et al. Repurposing of clinically approved drugs for treatment of coronavirus disease 2019 in a 2019-novel coronavirus (2019-nCoV) related coronavirus model. Chin Med J. 2020;133(9):1051-1056. doi:10.1097/CM9.0000000000000797
12. Balasubramanian A, Teramoto T, Kulkarni AA, Bhattacharjee AK, Padmanabhan R. Antiviral activities of selected antimalarials against dengue virus type 2 and Zika virus. Antiviral Res. 2017;137:141-150. doi:10.1016/j.antiviral.2016.11.015
13. Palmer KJ, Holliday SM, Brogden RN. Mefloquine. A review of its antimalarial activity, pharmacokinetic properties and therapeutic efficacy. Drugs. 1993;45(3):430-475. doi: 10.2165/00003495-199345030-00009
14. Karbwang J, White NJ. Clinical pharmacokinetics of mefloquine. Clin Pharmacokinet. 1990;19(4):264-279. doi:10.2165/00003088-199019040-00002
15. Taken T, Katoh Y, Doki T, Hohdatsu T. Effect of chloroquine on feline infectious peritonitis virus infection in vitro and in vivo. Antiviral Res. 2013;99(2):100-107. doi:10.1016/j.antiviral.2013.04.016
16. Lundstrom K. Coronavirus pandemic-therapy and vaccines. Biomedicines. 2020;8(5):109. doi:10.3390/biomedicines8050109
17. Takano T, Satoh K, Doki T, Tanabe T, Hohdatsu T. Antiviral effects of hydroxychloroquine and type I interferon on in vitro fatal feline coronavirus infection. Viruses. 2020;12(5):576. doi:10.3390/v12050576