Characterization of moxidectin against; Strongyloides ratti:; in vitro; and; in vivo; activity and pharmacokinetics in the rat model

Strongyloides stercoralis is a soil-transmitted helminth affecting an estimated 30-100 million people. Since the infection may be severe and life-threatening, accessible and effective treatment is pivotal. Currently, ivermectin is the drug of choice but has limitations. Moxidectin, a veterinary anthelminthic approved for use in human onchocerciasis, is a promising drug alternative against strongyloidiasis. In this study, we evaluated the in vitro activity of moxidectin on Strongyloides ratti larvae (L3) and adult females and the activity as well as the pharmacokinetics of moxidectin in S. ratti infected rats. In vitro, moxidectin had an activity that was similar to that of ivermectin, with median lethal concentration values for L3 and adults in the range of 0.08-1.44 muM, after 72 h of exposure. In vivo, doses of 250, 500, and 750 mug/kg of moxidectin resulted in a reduction of the worm burden ranging from 48.5 to 75%. At the highest dose (750 mug/kg) we observed a maximal blood concentration of 50.3 ng/mL and an area under the curve of 895.2 ng x h/mL. The half-life in rats was 9 h, and moxidectin was cleared to undetectable blood levels within 7 d (<10 ng/mL). No exposure-response relationship was observed. This work contributes to the characterization of moxidectin in the treatment of S. ratti as a model of Strongyloides spp. and, as such, supports moving moxidectin further along the drug development pipeline in the treatment of human strongyloidiasis.