Pharmacokinetics and safety of single and repeat doses of ceftibuten in healthy participants: a phase 1 dose escalation study.

Abstract

Ledaborbactam etzadroxil, the prodrug of the active β-lactamase inhibitor ledaborbactam, is being developed in combination with ceftibuten to treat serious infections caused by drug-resistant Enterobacterales. This study evaluated the safety and pharmacokinetics of ceftibuten in healthy adults at anticipated higher doses required, in combination with ledaborbactam etzadroxil, to treat Enterobacterales infections. Thirty-six participants (n = 12 per cohort [ceftibuten n = 9, placebo n = 3]) received a single oral dose of ceftibuten (400, 800, or 1,200 mg) or matched placebo on day 1. Following a one-day washout, the same participants received repeat oral doses of ceftibuten (400 mg once daily, 400 mg every 12 hours [q12h], or 400 mg q8h) for 10 days. Of the 36 participants, 25 (ceftibuten 67%, placebo 78%) reported 65 treatment-emergent adverse events (TEAEs). Nausea (22%), headache (15%), and fatigue (15%) were the most reported TEAEs among ceftibuten-treated participants. No participant experienced serious adverse events or discontinuations due to TEAEs. In both single- and multiple-dose cohorts, cis-ceftibuten isomer exposure was dose-proportional for areas under the curve (AUCs) but less than dose-proportional for maximum concentrations (C_max). Low levels of cis-ceftibuten accumulation were observed at steady state, with accumulation ratios of 1.06, 1.09, and 1.24 for the 400 mg once daily, q12h, and q8h cohorts, respectively. Cis-ceftibuten and trans-ceftibuten recovery in urine was 47% and 6%, respectively, following a single dose of 1,200 mg.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04314206.