Emodepside

The emergence and spread of anthelmintic resistance represent a major challenge for treating parasitic nematodes, threatening mass‐drug administration control programs in humans and zoonotic hosts. Currently, experimental evidence to understand the influence of management (e.g., treatment dose and frequency) and parasite‐associated factors (e.g., genetic variation, population size and mutation rates) is scarce. To rectify this knowledge gap, we performed controlled evolution experiments with the model nematode Caenorhabditis elegans and further evaluated the evolution dynamics with a computational model. Large population size was critical for rapid ivermectin resistance evolution in vitro and in silico. Male nematode production was favored during resistance evolution, suggesting a selective advantage of sexual recombination under drug pressure in vitro. Evolution of ivermectin resistance led to reduced efficacy of the structurally related anthelmintic moxidectin, as anticipated, as well as reduced efficacy of the structurally unrelated anthelmintic emodepside, which has a distinct mode of action. In contrast, albendazole, levamisole, and monepantel efficacy were not influenced by the evolution of ivermectin resistance. We conclude that combining computational modeling with in vitro evolution experiments to test specific aspects of evolution directly represents a promising approach to guide the development of novel treatment strategies to anticipate and mitigate resistance evolution in parasitic nematodes.

Drug release from four different formulations of the poorly soluble drug emodepside was determined in absence and presence of an absorptive sink (absorptive compartment separated by a barrier) by analyzing both molecularly dissolved and apparently dissolved drug concentrations in parallel. To this end, microdialysis and in situ 2nd derivative UV spectroscopy were employed. Two dose strengths each were investigated of crystalline conventional release tablets, pH-dependent hydroxypropyl methylcellulose acetate succinate-based amorphous solid dispersion (ASD) tablets, pH-independent polyvinylpyrrolidone vinyl acetate ASD tablets, and a polyethylene glycol 400 (PEG₄₀₀)-based oral solution. The presence of the absorptive sink did significantly increase the (molecularly dissolved) supersaturation in the case of the PEG₄₀₀-based oral solution as compared to previously published dissolution data while the supersaturation enhancement caused by the absorptive sink for the other formulations was moderate to marginal. This indicates that, for different formulation types, the dynamic interplay between dissolution, supersaturation, colloid-association, and precipitation is captured better by combined dissolution-permeation. Furthermore, the predictive potential of combined dissolution-permeation testing compared to mere dissolution testing was evaluated. The extent and duration of both molecular and apparent dissolution were compared to human plasma concentration time curves to establish in vitro in vivo correlation (IVIVC). Likewise, the initial flux as well as cumulative amount permeated across the PAMPA barrier of the dissolution-permeation assays were compared to human plasma concentration time curves to establish IVIVCs. While apparent dissolution yielded poor IVIVC, both molecular dissolution and dissolution-permeation yielded good and comparable IVIVCs. Finally, a refined mechanistic understanding is derived from the aforementioned dissolution and dissolution-permeation data to explain the observed differences.