Impact of renal impairment on pharmacokinetics, safety, and tolerability of funobactam, combined with imipenem and cilastatin.

A phase 1, open-label study was conducted to investigate the effect of renal impairment (RI) on pharmacokinetics (PK) and safety of funobactam plus imipenem/cilastatin. Participants were enrolled and assigned to one of five cohorts based on renal function category: normal renal function, mild RI, moderate RI, severe RI, and end-stage renal disease (ESRD) requiring hemodialysis (HD). Participants received a single-dose of funobactam with imipenem and cilastatin by intravenous infusion administered over 60 min. Serial blood and urine samples were collected for non-compartmental PK analysis. Compared to participants with normal renal function, the geometric mean ratio (90% confidence interval) of plasma area under the curve (AUC0-∞) for funobactam, imipenem, and cilastatin increased with RI from mild (1.32 [1.04, 1.66], 1.37 [1.04, 1.79], and 1.27 [0.90, 1.78], respectively) to ESRD requiring HD (9.58 [7.59, 12.10], 2.69 [2.06, 3.52], and 15.15 [10.8, 21.3], respectively). The renal clearance for funobactam, imipenem, and cilastatin decreased progressively from normal renal function (3.93 ± 1.12 L/h, 4.95 ± 2.40 L/h, and 6.98 ± 2.75 L/h, respectively) to severe RI (0.94 ± 0.37 L/h, 1.16 ± 0.34 L/h, and 1.70 ± 0.60 L/h, respectively). Plasma clearance of funobactam, imipenem, and cilastatin correlated (r ≥0.93) with creatinine clearance and the estimated glomerular filtration rate. The treatment was well tolerated, with no deaths, severe adverse events, or discontinuation due to adverse events. Dosage adjustments of funobactam, imipenem, and cilastatin will be needed in patients with renal impairment or ESRD requiring HD.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04787562.