A multi-center, open-label, two-part study to investigate the effect of renal function and hemodialysis on the pharmacokinetics of the novel β-lactamase inhibitor nacubactam.

Nacubactam is a novel bicyclic non-β-lactam β-lactamase inhibitor that acts as a penicillin-binding protein (PBP-2) active antibacterial, almost exclusively cleared by renal excretion. This study assessed the effect of renal function and hemodialysis on nacubactam pharmacokinetics following a single intravenous (IV) 1 g infusion. Part 1 included three subjects with normal renal function, and six each with mild, moderate, or severe renal impairment; Part 2 included eight subjects with end-stage renal disease undergoing hemodialysis. We observed a strong linear relationship between renal function and both nacubactam total clearance and renal clearance. Compared with subjects with normal renal function, mean nacubactam total clearance was 49%, 73%, and 85% lower among subjects with mild, moderate, and severe renal impairment, respectively, and renal clearance was 42%, 70%, and 90% lower. Nacubactam systemic exposure was correspondingly greater in subjects with impaired renal function. Compared with the normal renal function group, AUC0-inf was 2-fold, 3.7-fold, and 6.6-fold higher in the mild, moderate, and severe impairment groups, respectively. Similar results were observed across four different methods of estimating renal clearance. Nacubactam was cleared by hemodialysis, with more than 60% of a single dose eliminated during a 4-h dialysis session. Renal impairment had no apparent effect on the safety profile of nacubactam, and a single 1 g dose was well tolerated in all groups. These data can be used to underwrite nacubactam dosing recommendations for patients with impaired renal function, including those receiving renal replacement therapy.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT02975388.