Safety, tolerability and pharmacokinetics of emodepside, a potential novel treatment for onchocerciasis (river blindness), in healthy male subjects

Abstract

Emodepside is an anthelmintic, originally developed for veterinary use. We investigated in healthy subjects the safety, and pharmacokinetics of a liquid service formulation (LSF) and immediate release (IR) tablet of emodepside in 2 randomised, parallel-group, placebo-controlled, Phase I studies.Methods: Seventy-nine subjects in 10 cohorts in the single ascending dose study and 24 subjects in 3 ascending-dose cohorts in the multiple ascending dose study were enrolled. Emodepside as LSF was administered orally as single 1-40-mg doses and for 10 days as 5 or 10 mg once daily and 10-mg twice daily doses, respectively.Pharmacokinetics and safety were assessed up to 21 and 30 days, respectively. In addition, IR tablets containing 5 or 20 mg emodepside were tested in the single ascending dose study.Results: Emodepside as LSF was rapidly absorbed under fasting conditions, with dose-proportional increase in plasma concentrations at doses from 1 to 40 mg.Terminal half-life was > 500 hours. In the fed state, emodepside was absorbed more slowly but overall plasma exposure was not significantly affected. Compared to the LSF, the rate and extent of absorption was significantly lower with the tablets.Conclusions: Overall, emodepside had acceptable safety and tolerability profiles, no major safety concerns, after single oral administration of 20 mg as LSF and after multiple oral administration over 10 days at 5 and 10 mg OD and at 10 mg twice daily. For further clinical trials, the development of a tablet formulation overcoming the limitations observed in the present study with the IR tablet formulation is considered.

Emodepside targets SLO-1 channels of Onchocerca ochengi and induces broad anthelmintic effects in a bovine model of onchocerciasis

“…In addition, a reversible increase in blood glucose was observed in toxicological studies, which was triggered by a decrease in insulin and increase in glucagon excretion [ 83 ]. However, although catabolic dysfunctions comparable to a diabetic type I situation were reported in a rat model after prolonged, high-dose emodepside exposure (~4–5 mg/kg, over four weeks orally in diet, was defined as the no-observed-adverse-effect level [ 83 ]), it was not a dose-limiting effect in a recent first-in-human trial [ 54 ]. The minor impacts on blood glucose and insulin levels in humans were only observed under fasting conditions and were not considered as clinically significant or reported as an adverse event [ 83 ].…”

“…In this study, we refer to the lower doses (0.15 mg/kg, singly or repeated) as the “humanized dose”. This is a plausible dose based on the human phase I trial data (in which single doses of up to 40 mg, and twice-daily doses of 10 mg for up to 10 days, were administered [ 54 ]). Modelling and simulations were performed using Phoenix WinNonlin (Certara) version 6.4 or later.…”

“…The obtained parameter estimates were used as fixed input for the simulations of PK profiles in cattle after seven daily IV administrations of 0.15 mg/kg or 0.75 mg/kg, respectively. Non-compartmental analysis of the simulated PK profiles was also performed to assess the impact of emodepside accumulation and to compare the efficacious exposure in cattle with the efficacious exposure in humans [ 54 ].…”

Development of emodepside as a possible adulticidal treatment for human onchocerciasis—The fruit of a successful industrial–academic collaboration

“…As a result, emodepside is currently being evaluated for the treatment of human onchocerciasis within the scope of a drug development partnership between the Drugs for Neglected Diseases initiative (DNDi) and Bayer [47]. Phase I clinical trials have already been completed successfully [48], and a Phase II trial is planned in 2021.…”

“…In the single-(0.1 to 40 mg emodepside) and multiple-dose (5 or 10 mg) studies, an oral liquid formulation of emodepside was used, with the multidose escalation study also comparing emodepside 10 mg daily with 10 mg twice daily. In the bioavailability study, 2 immediate-release (IR) tablet emodepside formulations were compared with the liquid formulation (5 or 10 mg) [48]. As a liquid service formulation, emodepside was rapidly absorbed under fasting conditions, with dose-proportional increases in plasma concentrations at doses from 1 mg to 40 mg.…”