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

Frauke Assmus,Richard M Hoglund,Sabine Specht,Ivan Scandale,Frédéric Monnot,Joel Tarning

doi:10.1371/journal.pntd.0010219

Abstract

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.

Highlights

Onchocerciasis (‘River Blindness’) is a parasitic infection caused by the filarial worm Onchocerca volvulus, which is transmitted through repeated bites of infected blackflies
A total of 142 healthy male subjects were included in the pooled population pharmacokinetic analysis, with 47, 18 and 77 subjects contributing pharmacokinetic data from the single ascending dose study (SAD), multiple ascending dose study (MAD) and relative bioavailability study (RelBA) study, respectively
The numerical predictive check after administration of emodepside as Liquid servive formulation (LSF) oral solution resulted in 1.13% and 1.03% of observations below and above the simulated 95% prediction interval, respectively

Summary

Introduction

Onchocerciasis (‘River Blindness’) is a parasitic infection caused by the filarial worm Onchocerca volvulus, which is transmitted through repeated bites of infected blackflies The Global Burden of Disease Study estimated a prevalence of 20.9 million cases in 2017, with more than 99% thereof living in 31 countries in sub-Saharan Africa [1], and an estimated 205 million being at risk of infection [2]. Global efforts to control onchocerciasis as a public health problem have been ongoing for more than four decades [6–8] and have largely reduced the morbidity and burden of disease in the African and American region [2]. The cornerstone of control and elimination programs is ivermectin, which kills the microfilariae, and temporarily sterilizes the adult parasite. Ivermectin lacks macrofilaricidal activity and treatments need to be repeated once or twice per year for over a decade (during the life span of the adult worm), making implementation and widespread coverage extremely difficult. To accelerate the progress towards onchocerciasis elimination, a macrofilaricidal drug that kills the adult parasite is urgently needed. 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

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Conclusion