Single- and Multiple-dose Pharmacokinetics, Excretion, Metabolism, and Safety of the Antivirulence Agent Fluorothiazinone in Healthy Adults

Introduction: Fluorothiazinone (FT) is a novel antivirulence agent formulated as an immediate-release uncoated tablet, with demonstrated efficacy and safety against infections caused by drug-resistant Gram-negative bacteria. In this study, we evaluated the pharmacokinetics, excretion, metabolism, and safety of FT in healthy adults under single- and multiple-dose regimens. Methods: In a randomized study, participants received either a single 1800 mg oral dose of FT or multiple doses according to one of the following regimens: two doses within one day (900 or 1200 mg every 12 h) or 14 doses across 7 days (900 mg every 12 h). Pharmacokinetics, excretion and metabolic profiles were assessed using serial blood and urine sampling. Results: Twenty-nine participants completed the study. Dividing the total daily dose into two equal administrations extended FT's half-life and systemic exposure, representing the optimal dosing strategy. Steady-state pharmacokinetics were observed after 7 days of dosing, indicating extensive tissue distribution. Urinary recovery of unmetabolized FT was low, and identified metabolites are presented. Both single and multiple doses were well tolerated. Conclusion: FT, administered orally, was safe and well tolerated in healthy adults in both single and repeated dosing regimens. The pharmacokinetic data support the continued clinical development of FT, including its use in future phase II and III trials. FT's lack of impact on normal intestinal microflora further substantiates its potential as an antivirulence therapy. © 2025 Elsevier B.V., All rights reserved.