Drug development for the treatment of onchocerciasis: Population pharmacokinetic and adverse events modeling of emodepside

Author summaryOnchocerciasis ('River Blindness'), is a worm infection common in sub-Saharan Africa. More than 20 million people are suffering from the disease which can lead to disfiguring skin disease, visual impairment and permanent blindness. The currently recommended treatment is ivermectin, which kills the juvenile worms and reduces the severity of the symptoms, but fails to kill the adult worm. As a consequence, the treatment needs to be repeated for 10-15 years (life span of the adult worm), imposing a large burden on patients and communities. Hence, there is an urgent need for a new, safe and short-course drug that kills the adult worm and offers a rapid cure. Emodepside is a promising drug candidate which has recently been administered to healthy volunteers for the first time. In this study, we characterized the relationship between dose, systemic exposure in human and the probability of experiencing an adverse event. Modeling and simulation were used to propose a short-course dosing regimen which balances risks and benefits in order to achieve efficacy while maintaining safety. Our results support the further clinical development of emodepside thus contributing to onchocerciasis elimination efforts. BackgroundTo accelerate the progress towards onchocerciasis elimination, a macrofilaricidal drug that kills the adult parasite is urgently needed. Emodepside has shown macrofilaricidal activity against a variety of nematodes and is currently under clinical development for the treatment of onchocerciasis. The aims of this study were i) to characterize the population pharmacokinetic properties of emodepside, ii) to link its exposure to adverse events in healthy volunteers, and iii) to propose an optimized dosing regimen for a planned phase II study in onchocerciasis patients. Methodology / Principal findingsPlasma concentration-time profiles and adverse event data were obtained from 142 subjects enrolled in three phase I studies, including a single-dose, and a multiple-dose, dose-escalation study as well as a relative bioavailability study. Nonlinear mixed-effects modeling was used to evaluate the population pharmacokinetic properties of emodepside. Logistic regression modeling was used to link exposure to drug-related treatment-emergent adverse events (TEAEs). Emodepside pharmacokinetics were well described by a transit-absorption model, followed by a 3-compartment disposition model. Body weight was included as an allometric function and both food and formulation had a significant impact on absorption rate and relative bioavailability. All drug-related TEAEs were transient, and mild or moderate in severity. An increase in peak plasma concentration was associated with an increase in the odds of experiencing a drug-related TEAE of interest. Conclusions/SignificancePharmacokinetic modeling and simulation was used to derive an optimized, body weight-based dosing regimen, which allows for achievement of extended emodepside exposures above target concentrations while maintaining acceptable tolerability margins.