Safety and Pharmacokinetic Assessments of a Novel Ivermectin Nasal Spray Formulation in a Pig Model

Jorge Errecalde, Adrian Lifschitz, Graciela Vecchioli, Laura Ceballos, Francisco Errecalde, Mariana Ballent, Gustavo Marín, Martín Daniele, Esteban Turic, Eduardo Spitzer, Fernando Toneguzzo, Silvia Gold, Alejandro Krolewiecki, Luis Alvarez, Carlos Lanusse, Jorge Errecalde, Adrian Lifschitz, Graciela Vecchioli, Laura Ceballos, Francisco Errecalde, Mariana Ballent, Gustavo Marín, Martín Daniele, Esteban Turic, Eduardo Spitzer, Fernando Toneguzzo, Silvia Gold, Alejandro Krolewiecki, Luis Alvarez, Carlos Lanusse

Abstract

Recently published data indicates that high ivermectin (IVM) concentrations suppress in vitro SARS-CoV-2 replication. Nasal IVM spray administration may contribute to attaining high drug concentrations in nasopharyngeal tissue, a primary site of virus entrance/replication. The safety and pharmacokinetic performances of a novel IVM spray formulation were assessed in a pig model. Piglets received IVM either orally (0.2 mg/kg) or by one or two nasal spray doses. The overall safety, and histopathology of the IVM-spray application site tissues, were assessed. The IVM concentration profiles measured in plasma and respiratory tract tissues after the nasal spray were compared with those achieved after the oral administration. Animals tolerated well the nasal spray formulation. No local/systemic adverse events were observed. After nasal administration, the highest IVM concentrations were measured in nasopharyngeal and lung tissues. The nasal/oral IVM concentration ratios in nasopharyngeal and lung tissues markedly increased by repeating (12 h apart) the spray application. The fast attainment of high and persistent IVM concentrations in nasopharyngeal tissue is the main advantage of the nasal over the oral route. These original results support the undertaking of future clinical trials to evaluate the safety/efficacy of the nasal IVM spray application in the prevention and/or treatment of COVID-19.

Keywords: Covid 19; Ivermectin; Nasal-spray formulation.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1
Fig. 1
Mean ivermectin (IVM) concentration profiles in nasopharyngeal (NP) tissue, lung and plasma following administration of one intranasal (N-IVM-spray) dose to piglets. The insert shows the comparative IVM concentrations obtained between 2 and 6 h post spray administration.
Fig. 2
Fig. 2
Comparative ivermectin (IVM) concentrations in nasopharyngeal (NP) tissue, lung and plasma measured at 6 h after the oral and N-IVM-spray (one and two doses) treatments. The spray to oral IVM concentration ratios (values in brackets) are shown for each of the target tissues/plasma.

References

    1. Campbell W.C. Ivermectin and malaria-putting an elderly drug to a new test. Am J Trop Med Hyg. 2020;102:1.
    1. Lim L.E., Vilchèze C., Ng C., Jacobs W., Jr., Ramón-García S., Thompson C. Anthelmintic avermectins kill Mycobacterium tuberculosis, including multidrug-resistant clinical strains. Antimicrobial Agents Chemother. 2013;57:1040–1046.
    1. Tay M.Y., Fraser J.E., Chan W.K. Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor IVM. Antiviral Res. 2013;99:301–306.
    1. Ashraf S., Prichard R. IVM exhibits potent antimitotic activity. Vet Parasitol. 2016;226:1–4.
    1. Juarez M., Schcolnik-Cabrera A., Dueñas-Gonzalez A. The multitargeted drug IVM: from an antiparasitic agent to a repositioned cancer drug. Am J Cancer Res. 2018;8:317–331.
    1. Intuyod K., Hahnvajanawong C., Pinlaor P., Pinlaor S. Anti-parasitic drug IVM exhibits potent anticancer activity against gemcitabine-resistant cholangiocarcinoma in vitro. Anticancer Res. 2019;39:4837–4843.
    1. Yang S.N., AtkinsonSC, Wang C. The broad spectrum antiviral IVM targets the host nuclear transport importin α/β1 heterodimer. Antiviral Res. 2020;177:104760.
    1. Lundberg L., Pinkham C., Baer A. Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan Equine Encephalitis Virus replication. Antiviral Res. 2013;100:662–672.
    1. Götz V., Magar L., Dornfeld D. Influenza A viruses escapes from MxA restriction at the expense of efficient nuclear vRNASOPHARYNX import. Sci Rep. 2016;6:23138.
    1. Caly L., Druce J., Catton M., Jans D.A., Wagstaff K.M. The FDA-approved Drug IVM inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020;178:104787.
    1. Wagstaff K.M., Rawlinson S.M., Hearps A., Jans D.A. An AlphaScreen(R)-based assay for high-throughput screening for specific inhibitors of nuclear import. J Biomol Screen. 2011;16:192–200.
    1. Wagstaff K.M., Sivakumaran H., Heaton S.M., Harrich D., Jans D.A. IVM is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem J. 2012;443:851–856.
    1. Cepelowicz Rajter J., Sherman M.S., Fatteh N., Vogel F., Sacks J., Rajte J.J. Use of ivermectin is associated with lower mortality in hospitalized patients with coronavirus disease 2019: the ICON study. Chest. 2020 doi: 10.1016/j.chest.2020.10.009.
    1. Ahmed S., Karim M.M., Ross A.G. A five day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. Int J Infect Dis. 2020 doi: 10.1016/j.ijid.2020.11.191.
    1. Krolewiecki A., Lifschitz A., Moragas M. Antiviral effect of high-dose ivermectin in adults with COVID-19: a pilot randomised, controlled, open label, multicentre trial. 2020.
    1. Wölfel R., Corman V.M., Guggemos W. Virological assessment of hospilatalized patients with COVID-2019. Nature. 2020;581:465–469.
    1. Lifschitz A., Virkel G., Sallovitz J. Comparative distribution of ivermectin and doramectin to parasite location tissues in cattle. Vet Parasitol. 2000;87:327–338.
    1. Jermain B., Hanafin P.O., Cao Y., Lifschitz A., Lanusse C., Rao G. Development of a minimal physiologically-based pharmacokinetic model to simulate lung exposure in humans following oral administration of Ivermectin for COVID-19 drug repurposing. J Pharm Sci. 2020 doi: 10.1016/j.xphs.2020.08.024.
    1. Ji L., Cen J., Lin S. Study on the subacute inhalation toxicity of ivermectin TC in rats. Comp Med. 2016;26:70–74.
    1. Chaccour C., Abizanda G., Casellas A. Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats. Sci Rep. 2020;10(1):17073. doi: 10.1038/s41598-020-74084-y.
    1. VICH Guideline 9 . The European Agency for the Evaluaion of Medicinal Products (EMEA) 2001. Veterinary medicines and information technology unit.CVMP/VICH/595/98-FINAL.
    1. Chambers P.G., Grandin T., Heinz G., Srisuvan T. (FAO) Publishers; Thailand: 2001. Guidelines for Human Handling, Transport and Slaughter of livestock.Food and Agriculture Organisation.
    1. Gibaldi M., Perrier D. Revised and Expanded. second ed. Marcel Dekker; New York, USA: 1982. Pharmacokinetics; pp. 45–109.
    1. Fernández L., Velásquez M., Sua L.F. The porcine biomodel in translational medical research: from biomodel to human lung transplantation. Biomedica. 2019;39:300–313.
    1. Lees P., Cheng Z., Chambers M., Hennessy D., Abbott E.M. Pharmacokinetics and bioequivalence in the pig of two ivermectin feed formulations. J Vet Pharmacol Ther. 2013;36:350–357.
    1. Pasay C.J., Yakob L., Meredith H.R. Treatment of pigs with endectocides as a complementary tool for combating malaria transmission by Anopheles farauti (s.s.) in Papua New Guinea. Parasit Vectors. 2019;12:124.
    1. [Internet].Prophylactic ivermectin in COVID-19 contacts.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit