Large Impact of obesity on the disposition of ivermectin, moxidectin and
eprinomectin in a canine model: relevance for COVID-19 patients.
Background and Purpose: Based on in vitro data, ivermectin (IVM) has
been proposed for the prevention and treatment of COVID-19, a condition
for which obesity is a major risk factor. 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 and two analog compounds, moxidectin (MOX) and
eprinomectin (EPR). Experimental Approach: An experimental model of
obesity in dogs was based on a high calorie diet. IVM, MOX and EPR were
administered intravenously, simultaneously in combination, to a single
group of dogs in two circumstances, during a control period and when
body weight had been increased by 50%. Key Results: In obese dogs,
clearance, expressed in absolute values (L/day), was not modified for
MOX and reduced for IVM and EPR, compared to the initial control state.
When scaled by body weight (L/day/kg), plasma clearance was reduced by
42, 55 and 63%, for MOX, IVM and EPR, respectively. In contrast, the
steady-state volume of distribution was markedly increased in absolute
values (L) by obesity. Conclusion and Implications: For IVM and MOX, the
obese dog model suggests that the maintenance dose should not be
adjusted by total body weight in the obese subject but should be based
on lean body weight. On the other hand, the loading dose should be
computed based on the total body weight of the obese subject.