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The standardized protocol does not exist, but it is agreed that the intravenous (i.v.) route is more effective than the others, especially the intramuscular (i.m.) route, based on the monitoring of venom\/antivenom pharmacokinetics in the systemic circulation. Recent evidence suggests that the lymphatic system may be crucial in abolishing venom action. Methods: A preclinical study was performed to determine the optimal administration route with emphasis on venom\/antivenom interplay in both the blood and lymph of experimentally envenomed sheep. Timed level measurements were used to compare the antivenom effect on the decrement of venom quantities in both relevant body compartments. Hematological and coagulation parameters, as well as proportions of developed anti-antivenom IgGs, were evaluated. Results: The i.m. antivenom resulted in faster and greater lymphatic absorption and complete neutralization of the venom, whereas the i.v. antivenom only slowed its absorption. The total amount of venom reaching the lymph (AUC0-t) was two times lower after i.m. administration. In the systemic circulation, i.m. antivenom had a lower peak concentration (cmax) and a longer time to reach it (tmax). However, the total venom exposure was three times lower than with i.v. antivenom. Irrespective of the treatment approach, both groups showed improvement in blood disorders with no significant difference in humoral response against equine F(ab\u2019)2 fragments. Conclusions:\u00a0I.m. administration proved to be a viable option for the snakebite management.<\/jats:p>","DOI":"10.3390\/pharmaceutics17020212","type":"journal-article","created":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T04:00:28Z","timestamp":1738900828000},"page":"212","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Pharmacokinetics of Snake Antivenom Following Intravenous and Intramuscular Administration in Envenomed Large Animal Model"],"prefix":"10.3390","volume":"17","author":[{"given":"Erika","family":"Gamulin","sequence":"first","affiliation":[{"name":"Centre for Research and Knowledge Transfer in Biotechnology, University of Zagreb, Rockefellerova 10, HR-10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanja","family":"Mateljak Luka\u010devi\u0107","sequence":"additional","affiliation":[{"name":"Centre for Research and Knowledge Transfer in Biotechnology, University of Zagreb, Rockefellerova 10, HR-10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2786-0054","authenticated-orcid":false,"given":"Maja","family":"Lang Balija","sequence":"additional","affiliation":[{"name":"Centre for Research and Knowledge Transfer in Biotechnology, University of Zagreb, Rockefellerova 10, HR-10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Smajlovi\u0107","sequence":"additional","affiliation":[{"name":"Clinic for Surgery, Orthopaedics and Ophthalmology, Faculty of Veterinary Medicine, University of Zagreb, Heinzelova 55, HR-10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dra\u017een","family":"Vnuk","sequence":"additional","affiliation":[{"name":"Clinic for Surgery, Orthopaedics and Ophthalmology, Faculty of Veterinary Medicine, University of Zagreb, Heinzelova 55, HR-10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jadranka","family":"Gulan Harcet","sequence":"additional","affiliation":[{"name":"Croatian Institute of Transfusion Medicine, Petrova 3, HR-10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"Tomi\u010di\u0107","sequence":"additional","affiliation":[{"name":"Croatian Institute of Transfusion Medicine, Petrova 3, HR-10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"He\u0107imovi\u0107","sequence":"additional","affiliation":[{"name":"Croatian Institute of Transfusion Medicine, Petrova 3, HR-10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7370-0997","authenticated-orcid":false,"given":"Beata","family":"Halassy","sequence":"additional","affiliation":[{"name":"Centre for Research and Knowledge Transfer in Biotechnology, University of Zagreb, Rockefellerova 10, HR-10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tihana","family":"Kurtovi\u0107","sequence":"additional","affiliation":[{"name":"Centre for Research and Knowledge Transfer in Biotechnology, University of Zagreb, Rockefellerova 10, HR-10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.idc.2018.10.001","article-title":"Venomous Bites, Stings, and Poisoning: An Update","volume":"33","author":"Warrell","year":"2019","journal-title":"Infect. 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