Evaluation of drug-drug interaction between nacubactam and β-lactam antibiotic (cefepime, aztreonam, meropenem, or piperacillin) in Japanese healthy participants

ABSTRACT We conducted an open-label study to assess the pharmacokinetics, safety, and tolerability of nacubactam—a β-lactamase inhibitor—administered alone or in combination with β-lactam antibiotic. Japanese healthy male participants received a single dose of nacubactam 2 g on Day 1, a single dose of β-lactam antibiotic (cefepime 2 g, aztreonam 2 g, meropenem 2 g, and piperacillin 4 g in Cohorts 1, 2, 3, and 4, respectively) on Day 3, and the combination of nacubactam and β-lactam antibiotic on Day 5. The study drugs were intravenously administered over 60 min. A total of 32 participants (8 in each cohort) were enrolled in the study. All participants completed the study and were included in the analysis. Exposures to nacubactam or β-lactam antibiotic (maximum plasma concentration [ C max ], area under the plasma concentration-time curve from time zero to the last quantifiable time [AUC 0−t ], and AUC from time zero to infinity [AUC 0−∞ ]) were similar between the treatment periods (monotherapy vs combination therapy) in all cohorts. Coadministration of nacubactam and β-lactam antibiotic did not affect the pharmacokinetic profile of nacubactam or β-lactam antibiotic with the 90% confidence intervals for the geometric least squares mean ratios (combination therapy/monotherapy) of C max , AUC 0−t , and AUC 0−∞ contained within the equivalence range of 0.80 to 1.25 for all study drugs. Nacubactam and β-lactam antibiotics were well tolerated. All treatment emergent adverse events were mild in severity and resolved without treatment. Our results support the further clinical development of nacubactam coadministered with these β-lactam antibiotics.