A Large Impact of Obesity on the Disposition of Ivermectin, Moxidectin and Eprinomectin in a Canine Model: Relevance for COVID-19 Patients
Alain Bousquet-Mélou, Anne Lespine, Jean-François Sutra, Isabelle Bargues, Pierre-Louis Toutain
Frontiers in Pharmacology, doi:10.3389/fphar.2021.666348
Ivermectin (IVM) and moxidectin (MOX) are used extensively as parasiticides in veterinary medicine. Based on in vitro 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.
ETHICS STATEMENT The animal study was reviewed and approved. No specific animal experiments were carried out. The publication is based on a more advanced and focused analysis of data published in 2009 in the form of a Meeting Abstract and which was incorporated in a pharmacy thesis defended in 2011. All animal procedures were conducted in accordance with accepted standards of humane animal care required at that time under agreement number 31-242 for animal experimentation from the French Ministry of Agriculture.
AUTHOR CONTRIBUTIONS AB-M was responsible for the study design and contributed to data analysis and interpretation. AL and J-FS were responsible for analytical quantification of the investigated substances. IB conducted the animal phase and managed the data sets. P-LT contributed to data analysis and interpretation and he wrote the first draft of the manuscript. All co-authors made intellectual input into the study and critically reviewed several drafts of the manuscript.
SUPPLEMENTARY MATERIAL The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2021.666348/ full#supplementary-material Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Copyright © 2021 Bousquet-Mélou, Lespine, Sutra, Bargues and Toutain. This is an open-access article distributed under..
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