Caenorhabditis elegans as a valuable model for the study of anthelmintic pharmacodynamics and drug-drug interactions: The case of ivermectin and eprinomectin.

Abstract

Caenorhabditis elegans is a free-living nematode that has been validated for anthelmintic drug screening. However, this model has not been used to address anthelmintic dose-response-time and drug-drug interactions through matrix array methodology. Eprinomectin (EPM) and Ivermectin (IVM) are macrocyclic lactones widely used as anthelmintics. Despite being very similar, EPM and IVM are combined in commercial formulations or mixed by farmers, under the assumption that the combination would increase their efficacy. However, there is no data reported on the pharmacological evaluation of the combination of both drugs. In this study, we assessed the pharmacodynamics and drug-drug interactions of these two anthelmintic drugs. Since the action of these drugs causes worm paralysis, we used an infrared motility assay to measure EPM and IVM effects on worm movement over time. The results showed that EPM was slightly more potent than IVM, that drug potency increased with drug time exposure, and that once paralyzed, worms did not recover. Different EPM/IVM concentration ratios were used and synergy and combination sensitivity scores were determined at different exposure times, applying Highest Single Agent (HSA), Loewe additivity, Bliss and Zero Interaction Potency (ZIP) models. The results clearly indicate that there is neither synergy nor antagonism between both macrocyclic lactones. This study shows that it is more relevant to prioritize the exposure time of each individual drug than to combine them to improve their effects. The results highlight the utility of C. elegans to address pharmacodynamics studies, particularly for drug-drug interactions. Models in vitro can be integrated to facilitate preclinical and clinical translational studies and help researchers to understand drug-drug interactions and achieve rational therapeutic regimes.