A Large Impact of Obesity on the Disposition of Ivermectin, Moxidectin and Eprinomectin in a Canine Model: Relevance for COVID-19 Patients

DOI record: { "DOI": "10.3389/fphar.2021.666348", "ISSN": [ "1663-9812" ], "URL": "http://dx.doi.org/10.3389/fphar.2021.666348", "abstract": "<jats:p>Ivermectin (IVM) and moxidectin (MOX) are used extensively as parasiticides in veterinary medicine. Based on <jats:italic>in vitro</jats:italic> data, IVM has recently been proposed for the prevention and treatment of COVID-19 infection, a condition for which obesity is a major risk factor. In patients, IVM dosage is based on total body weight and there are no recommendations to adjust dosage in obese patients. The objective of this study was to establish, in a canine model, the influence of obesity on the clearance and steady-state volume of distribution of IVM, MOX, and a third analog, eprinomectin (EPR). An experimental model of obesity in dogs was based on a high calorie diet. IVM, MOX, and EPR were administered intravenously, in combination, to a single group of dogs in two circumstances, during a control period and when body weight had been increased by 50%. In obese dogs, clearance, expressed in absolute values (L/day), was not modified for MOX but was reduced for IVM and EPR, compared to the initial control state. However, when scaled by body weight (L/day/kg), plasma clearance was reduced by 55, 42, and 63%, for IVM, MOX and EPR, respectively. In contrast, the steady-state volume of distribution was markedly increased, in absolute values (L), by obesity. For IVM and MOX, this obese dog model suggests that the maintenance doses in the obese subject should be based on lean body weight rather than total weight. On the other hand, the loading dose, when required, should be based on the total body weight of the obese subject.</jats:p>", "alternative-id": [ "10.3389/fphar.2021.666348" ], "author": [ { "affiliation": [], "family": "Bousquet-Mélou", "given": "Alain", "sequence": "first" }, { "affiliation": [], "family": "Lespine", "given": "Anne", "sequence": "additional" }, { "affiliation": [], "family": "Sutra", "given": "Jean-François", "sequence": "additional" }, { "affiliation": [], "family": "Bargues", "given": "Isabelle", "sequence": "additional" }, { "affiliation": [], "family": "Toutain", "given": "Pierre-Louis", "sequence": "additional" } ], "container-title": "Frontiers in Pharmacology", "container-title-short": "Front. Pharmacol.", "content-domain": { "crossmark-restriction": true, "domain": [ "frontiersin.org" ] }, "created": { "date-parts": [ [ 2021, 5, 20 ] ], "date-time": "2021-05-20T07:29:52Z", "timestamp": 1621495792000 }, "deposited": { "date-parts": [ [ 2021, 5, 20 ] ], "date-time": "2021-05-20T07:30:03Z", "timestamp": 1621495803000 }, "indexed": { "date-parts": [ [ 2022, 4, 14 ] ], "date-time": "2022-04-14T15:53:07Z", "timestamp": 1649951587163 }, "is-referenced-by-count": 1, "issued": { "date-parts": [ [ 2021, 5, 20 ] ] }, "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2021, 5, 20 ] ], "date-time": "2021-05-20T00:00:00Z", "timestamp": 1621468800000 } } ], "link": [ { "URL": "https://www.frontiersin.org/articles/10.3389/fphar.2021.666348/full", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "1965", "original-title": [], "prefix": "10.3389", "published": { "date-parts": [ [ 2021, 5, 20 ] ] }, "published-online": { "date-parts": [ [ 2021, 5, 20 ] ] }, "publisher": "Frontiers Media SA", "reference": [ { "DOI": "10.1016/0378-4347(95)00294-5", "article-title": "Determination of Moxidectin in Plasma by High-Performance Liquid Chromatography with Automated Solid-phase Extraction and Fluorescence Detection", "author": "Alvinerie", "doi-asserted-by": "publisher", "first-page": "119", "journal-title": "J. 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