Single-Dose Pharmacokinetics and Safety of Meropenem-Vaborbactam in Subjects with Chronic Renal Impairment

Abstract

Vaborbactam is a member of a new class of β-lactamase inhibitors with inhibitory activity against serine carbapenemases (e.g., Klebsiella pneumoniae carbapenemase) that has been developed in combination with meropenem. The pharmacokinetics of the combination was evaluated in 41 subjects with chronic renal impairment in a phase 1, open-label, single-dose study. Subjects were assigned to one of five groups based on renal function: normal (creatinine clearance of ≥90 ml/min), mild (estimated glomerular filtration rate [eGFR] of 60 to 89 ml/min/1.73 m2), moderate (eGFR of 30 to <60), or severe (eGFR of <30) impairment plus end-stage renal disease (ESRD) patients on hemodialysis. Subjects received a single intravenous dose of 1 g of meropenem plus 1 g of vaborbactam by 3-h infusion. The ESRD group received two doses (on and off dialysis) separated by a washout. Pharmacokinetic parameters were estimated by standard noncompartmental methods. For both meropenem and vaborbactam, the area under the concentration-time curve was larger and the elimination half-life was longer with decreasing renal function. Meropenem and vaborbactam total plasma clearance (CLt) rates were similar and decreased with decreasing renal function. Slopes of the linear relationship between eGFR and CLt were similar, indicating a similar proportional reduction in CLt with decreasing renal function. Hemodialysis significantly increased drug clearance of meropenem (mean of 2.21-fold increase in CLt, P < 0.001) and vaborbactam (mean of 5.11-fold increase, P = 0.0235) relative to drug administration off dialysis, consistent with dose recovery rates of 38.3% and 52.9% for meropenem and vaborbactam, respectively, in dialysate. Plasma clearance of meropenem and vaborbactam is reduced with renal impairment, requiring dose adjustment. Hemodialysis removes both drugs. (This study has been registered at ClinicalTrials.gov under identifier NCT02020434.).

Keywords: hemodialysis; meropenem-vaborbactam; pharmacokinetics; renal impairment.

Copyright © 2018 American Society for Microbiology.

Figures

FIG 1

Plots of median meropenem (A) and vaborbactam (B) concentration-time profiles, stratified by renal impairment group and timing relative to dialysis (for end-stage renal disease subjects).

FIG 2

Relationship between estimated glomerular filtration rate (eGFR) and total plasma clearance (CLt) (A) and renal clearance (CLr) (B) of meropenem and vaborbactam. Linear regression analyses were conducted separately for the two drugs. Data are only included from groups 1 through 4 and group 5 on dialysis.

FIG 3

Effect of hemodialysis on plasma clearance (CLt) of meropenem and vaborbactam patients with ESRD. Values in the figure are on-dialysis/off-dialysis ratios of CLt values. P values were generated using a single-sample t test of the ratio (on-dialysis/off-dialysis). Data are from group 5 only.