Discussion
acute liver injury
ADVERSE EVENTS, LIVER FAILURE, ONCHOCERCIASIS, DRUG-INDUCED LIVER INJURY, LYMPHATIC FILARIASIS
Via its anti-Across all three parts of the study, the PK findings showed good bioavailability of flubentylosin in human subjects, with rapid absorption and sustained exposure over its acceptably long half-life, following single- and multiple-dose administration. Exposure increased in a slightly more than dose-proportional manner across the doses. Multiple-dose administration yielded similar blood flubentylosin concentrations on Day 1 and Day 14. Flubentylosin concentrations also appeared to be similar under fasting and fed conditions, which would be a desirable attribute for a drug that will likely be used in settings where consistent dosing with relation to food cannot be assured.Overall, the safety profile of flubentylosin in human subjects was good at doses up to and including 400 mg QD for 14 days. The majority of the reported AEs were mild to or moderate. No flubentylosin-related serious adverse events were reported. The asymptomatic and reversible increases in ALT and/or AST seen after a single 1000-mg dose of flubentylosin were not present in subjects given multiple doses of flubentylosin up to 400 mg QD for 14 days. None of the subjects with ALT and/or AST elevations had concurrent bilirubin elevations, which indicate severe drug-induced liver injury, and none developed severe and/or life-threatening outcomes such as liver failure.Flubentylosin is a macrolide antibacterial, a widely used therapeutic class that has been found to be associated with acute liver injury, initially in spontaneous reports and case series, and more recently in a systematic review and meta-analysis [Thus, this three-part, first-in-human Phase-I study provided valuable information on the safety, PK profile, dose proportionality and linearity of flubentylosin in healthy human subjects, as well as the food effect. It also enabled us to identify a dose and dosing regimens, i.e. 400 mg of flubentylosin for 7 or 14 days, that are expected to achieve efficacious exposures and provide an adequate safety margin. If safety and antifilarial activity are confirmed in clinical trials, an effective therapy for onchocerciasis and/or lymphatic filariasis that requires no more than 14 days of dosing would be a substantial improvement on currently available treatments. Phase-II studies using these regimens in patients with onchocerciasis are currently ongoing.