Faecal pharmacokinetics, microbiome, and bile acid changes in healthy subjects given intravenous followed by oral omadacycline; a Phase 1 clinical trial.

Background: There is an urgent need to develop new antimicrobials effective intravenously for Clostridioides difficile infection (CDI). Omadacycline is an aminomethylcycline tetracycline available orally and intravenously with potent in vitro activity against C. difficile and a low propensity to cause CDI. The purpose of this study was to assess the safety, faecal pharmacokinetics, microbiome and bile acid changes in healthy subjects given a course of intravenous omadacycline with oral omadacycline step down after 5 days.

Methods: This Phase 1, open-label study was conducted in healthy volunteers 18-40 years. Subjects received a 5-day course of omadacycline given intravenously followed by 5 days of oral omadacycline. Stool samples were analysed for omadacycline concentrations, gut microbiome changes and bile acid changes from baseline.

Results: Eight healthy volunteers aged 30 ± 4 years (50% Female) were recruited and all completed therapy. All subjects had detectable omadacycline stool concentrations after 48 hours of intravenous dosing and averaged 195 ± 97 µg/g (mean ± SD) by day 5. Omadacycline concentrations increased rapidly after the start of oral therapy on day 6 with average concentrations of 854 ± 404 µg/g of stool by day 10. Microbiome and bile acid evaluations showed preservation of key microbiome taxa that confer health benefit and preservation of bile acid homeostasis.

Conclusion: Intravenous omadacycline followed by oral step-down administration in healthy adults achieved high faecal concentrations while preserving key bacterial species and bile acid homeostasis in the gut. These findings support Phase 2 studies directed towards the development of omadacycline as a CDI-targeted antibiotic.