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
Journal of Pharmaceutical Sciences, doi:10.1016/j.xphs.2021.01.017
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 IVMspray 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.
Author Contributions J. Errecalde. Protocol design, IVM spray design. Animal phase work (Spray administration and sampling). Data analysis. Overall integration/discussion of the data. Manuscript writing. A. Lifschitz. Protocol design. HPLC analysis. PK data analysis. Overall integration/discussion of the data. Manuscript writing. G. Vecchioli.
References
Ahmed, Karim, Ross, A five day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness, Int J Infect Dis,
doi:10.1016/j.ijid.2020.11.191Andez, Vel Asquez, Sua, The porcine biomodel in translational medical research: from biomodel to human lung transplantation, Biomedica
Ashraf, Prichard, IVM exhibits potent antimitotic activity, Vet Parasitol
Caly, Druce, Catton, Jans, Wagstaff, The FDA-approved Drug IVM inhibits the replication of SARS-CoV-2 in vitro, Antiviral Res
Campbell, Ivermectin and malaria-putting an elderly drug to a new test, Am J Trop Med Hyg
Chaccour, Abizanda, Casellas, Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats, Sci Rep,
doi:10.1038/s41598-020-74084-yChambers, Grandin, Heinz, Srisuvan, Guidelines for Human Handling, Transport and Slaughter of livestock
Gibaldi, Perrier, Pharmacokinetics. In: Revised and Expanded
G€ Otz, Magar, Dornfeld, Influenza A viruses escapes from MxA restriction at the expense of efficient nuclear vRNASOPHARYNX import, Sci Rep
Intuyod, Hahnvajanawong, Pinlaor, Pinlaor, Anti-parasitic drug IVM exhibits potent anticancer activity against gemcitabine-resistant cholangiocarcinoma in vitro, Anticancer Res
Jermain, Hanafin, Cao, Lifschitz, Lanusse et al., 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,
doi:10.1016/j.xphs.2020.08.024Ji, Cen, Lin, Study on the subacute inhalation toxicity of ivermectin TC in rats, Comp Med
Juarez, Schcolnik-Cabrera, Dueñas-Gonzalez, The multitargeted drug IVM: from an antiparasitic agent to a repositioned cancer drug, Am J Cancer Res
Krolewiecki, Lifschitz, Moragas, controlled, open label
Lees, Cheng, Chambers, Hennessy, Abbott, Pharmacokinetics and bioequivalence in the pig of two ivermectin feed formulations, J Vet Pharmacol Ther
Lifschitz, Virkel, Sallovitz, Comparative distribution of ivermectin and doramectin to parasite location tissues in cattle, Vet Parasitol
Lim, Vilch Eze, Ng, Jr, On-García et al., Anthelmintic avermectins kill Mycobacterium tuberculosis, including multidrugresistant clinical strains, Antimicrobial Agents Chemother
Lundberg, Pinkham, Baer, Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan Equine Encephalitis Virus replication, Antiviral Res
Pasay, Yakob, Meredith, Treatment of pigs with endectocides as a complementary tool for combating malaria transmission by Anopheles farauti (s.s.) in Papua New Guinea, Parasit Vectors
Rajter, Sherman, Fatteh, Vogel, Sacks et al., Use of ivermectin is associated with lower mortality in hospitalized patients with coronavirus disease 2019: the ICON study,
doi:10.1016/j.chest.2020.10.009Tay, Fraser, Chan, Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor IVM, Antiviral Res
Wagstaff, Rawlinson, Hearps, Jans, An AlphaScreen(R)-based assay for high-throughput screening for specific inhibitors of nuclear import, J Biomol Screen
Wagstaff, Sivakumaran, Heaton, Harrich, Jans, IVM is a specific inhibitor of importin a/b-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus, Biochem J
W€ Olfel, Corman, Guggemos, Virological assessment of hospilatalized patients with COVID-2019, Nature
Yang, Atkinsonsc, Wang, The broad spectrum antiviral IVM targets the host nuclear transport importin a/b1 heterodimer, Antiviral Res
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"author": "Chaccour",
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"key": "10.1016/j.xphs.2021.01.017_bib22",
"series-title": "Guidelines for Human Handling, Transport and Slaughter of livestock.Food and Agriculture Organisation",
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"article-title": "Pharmacokinetics",
"author": "Gibaldi",
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{
"DOI": "10.1111/j.1365-2885.2012.01428.x",
"article-title": "Pharmacokinetics and bioequivalence in the pig of two ivermectin feed formulations",
"author": "Lees",
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"volume": "36",
"year": "2013"
},
{
"DOI": "10.1186/s13071-019-3392-0",
"article-title": "Treatment of pigs with endectocides as a complementary tool for combating malaria transmission by Anopheles farauti (s.s.) in Papua New Guinea",
"author": "Pasay",
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