Plasma and intrapulmonary pharmacokinetics of ceftibuten and ledaborbactam in healthy male and female adults

ABSTRACT Ledaborbactam etzadroxil (LED-E) is an oral prodrug of ledaborbactam, a broad-spectrum β-lactamase inhibitor. In combination with ceftibuten (CTB), a third-generation oral cephalosporin, LED-E represents a potential oral β-lactam/β-lactamase inhibitor regimen for treating infections caused by drug-resistant Gram-negative pathogens. This phase 1, single-center, open-label study evaluated intrapulmonary concentrations of ledaborbactam (LED) and CTB in healthy adults. Participants in Group 1 received five oral doses of CTB/LED-E (600 mg/600 mg) every 12 h (q12h), and participants in Group 2 received five oral doses of CTB 600 mg q12h. Following the fifth dose, participants underwent a standardized single bronchoscopy with bronchoalveolar lavage (BAL). Twenty-eight participants in Group 1 and six participants in Group 2 were randomized and dosed. Among participants receiving CTB/LED-E, epithelial lining fluid (ELF) area under the concentration-time curve from 0 to 12 h (AUC 0–12 ) for aspirate 1 was 14,867 ng·h/mL for CTB and 14,529 ng·h/mL for LED, and for pooled aspirates 2 + 3 + 4 was 10,486 ng·h/mL and 9,809 ng·h/mL, respectively. ELF-to-unbound plasma AUC ratios were 0.341 (aspirate 1) and 0.239 (pooled aspirates 2 + 3 + 4) for CTB and 1.560 and 1.032, respectively, for LED. Participants receiving CTB alone demonstrated similar lung penetration, indicating no effect of LED on CTB exposure. Both CTB/LED-E and CTB alone were safe and well tolerated; all adverse events were mild or moderate and unrelated to study drug. These results demonstrate pulmonary penetration of CTB and LED and support further evaluation of CTB/LED-E for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens. This study is registered with ClinicalTrials.gov as NCT06665555 .