Evidence of intrapulmonary penetration of nacubactam, a novel β-lactamase inhibitor, following coadministration of nacubactam with meropenem in healthy adults

Nacubactam is a novel non-β-lactam β-lactamase inhibitor being developed in combination with β-lactam antibiotics to treat serious gram-negative bacterial infections including nosocomial pneumonia. This study evaluated the systemic and intrapulmonary pharmacokinetics and safety of nacubactam plus meropenem in healthy adult male and female volunteers. Post-treatment bronchoalveolar lavage (BAL) to collect lung epithelial lining fluid (ELF). A total of 21 healthy adult participants were enrolled to receive a single dose of nacubactam 2 g coadministered with meropenem 2 g, of whom 20 underwent BAL and collection of blood samples for plasma pharmacokinetic (PK) characterization. The ratios of ELF to plasma area under the concentration-time curve from 0 to 8 h were 0.271 for nacubactam and 0.183 for meropenem. The estimated nacubactam half-life in ELF was 1.82 h and that in plasma was 1.71 h. PK data for meropenem were aligned with previously published results, with lower concentrations in ELF compared with plasma. The intrapulmonary penetration of nacubactam was favorable, with an area under the curve ratio (epithelial lining fluid to plasma) of 0.271, which was comparable to or greater than that observed for other approved β-lactamase inhibitors. The treatment combination was well tolerated, and no significant safety signals were identified. These data support further consideration of nacubactam/β-lactam combinations for the treatment of serious nosocomial pneumonia.CLINICAL TRIALSThis study was registered with ClinicalTrials.gov as NCT03182504.