Pharmacokinetics, safety, and tolerability of ceftibuten-ledaborbactam etzadroxil in participants with renal impairment

Ledaborbactam etzadroxil is an orally bioavailable prodrug of ledaborbactam, a broad-spectrum β-lactamase inhibitor being developed in combination with ceftibuten for the treatment of complicated urinary tract infections caused by antibiotic-resistant pathogens. As both agents are primarily eliminated via renal excretion, dose adjustment may be required in patients with impaired renal function. This phase 1 study (NCT05488678) evaluated the pharmacokinetics and safety of ceftibuten and ledaborbactam etzadroxil in participants with normal renal function; mild, moderate, or severe renal impairment; or end-stage renal disease (ESRD) undergoing hemodialysis. Participants received a single dose of ceftibuten-ledaborbactam etzadroxil (600 mg/600 mg); those with ESRD received doses both before and after hemodialysis. Among 32 enrolled participants, the mean age was 62.2 years, and 81.3% were male. For both ceftibuten and ledaborbactam, decreasing renal function was associated with increased plasma exposure and reduced renal clearance (CLr). In participants with mild, moderate, or severe renal impairment, plasma exposure of ceftibuten increased 1.3-, 2.3-, and 3.7-fold, respectively, and ledaborbactam increased 1.5-, 1.9-, and 4.4-fold, respectively. Ceftibuten CLr decreased from 2.2 L/h in participants with normal function to 0.3 L/h in those with severe impairment, while ledaborbactam CLr decreased from 3.0 to 0.5 L/h. In participants with ESRD, both drugs were moderately removed (23% and 38% for ceftibuten and ledaborbactam, respectively) by hemodialysis. No deaths, serious adverse events, or treatment-related adverse events leading to study drug discontinuation were reported. These results indicate that dose adjustment of ceftibuten-ledaborbactam etzadroxil will be required for patients with reduced renal function.This study is registered with ClinicalTrials.gov as NCT05488678.