Plasma and Intrapulmonary Concentrations of ETX2514 and Sulbactam following Intravenous Administration of ETX2514SUL to Healthy Adult Subjects

Abstract

ETX2514 is a novel β-lactamase inhibitor that broadly inhibits Ambler class A, C, and D β-lactamases. ETX2514 combined with sulbactam (SUL) in vitro restores sulbactam activity against Acinetobacter baumannii ETX2514-sulbactam (ETX2514SUL) is under development for the treatment of A. baumannii infections. The objective of this study was to determine and compare plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations following intravenous (i.v.) ETX2514 and sulbactam. Plasma, ELF, and AM concentrations of ETX2514 and sulbactam were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 30 healthy adult subjects following repeated dosing (ETX2514 [1 g] and sulbactam [1 g] every 6 h [q6h], as a 3-h i.v. infusion, for a total of 3 doses). A bronchoalveolar lavage (BAL) was performed once in each subject at either 1, 2.5, 3.25, 4, or 6 h after the start of the last infusion. Penetration ratios were calculated from area under the concentration-time curve from 0 to 6 h (AUC0-6) values for total plasma and ELF using mean and median concentrations at the BAL fluid sampling times. Respective ELF AUC0-6 values, based on mean and median concentrations, were 40.1 and 39.4 mg · h/liter for ETX2514 and 34.7 and 34.5 mg · h/liter for sulbactam. Respective penetration ratios of ELF to total/unbound plasma concentrations, based on mean and median AUC0-6 values, of ETX2514 were 0.37/0.41 and 0.36/0.40, whereas these same ratio values were 0.50/0.81 and 0.50/0.80 for sulbactam. ETX2514 and sulbactam concentrations in AM were measurable and fairly constant throughout the dosing interval (median values of 1.31 and 1.01 mg/liter, respectively). These data support further study of ETX2514SUL for the treatment of pneumonia caused by multidrug-resistant A. baumannii (This study has been registered at ClinicalTrials.gov under identifier NCT03303924.).

Keywords: ETX2514; ETX2514SUL; alveolar macrophages; epithelial lining fluid; pharmacokinetics; sulbactam.

Copyright © 2018 American Society for Microbiology.

Figures

FIG 1

Mean (± SD) plasma concentration versus time profiles of ETX2514 and sulbactam with the third dose of ETX2514SUL (1 g ETX2514, 1 g sulbactam) administered as a 3-h i.v. infusion every 6 h. Shaded region represents the 3-h infusion period. The y axis is log scale.

FIG 2

Individual concentrations of ETX2514 in plasma, epithelial lining fluid (ELF), and alveolar macrophages (AM) at the BAL fluid sampling times after the third dose of ETX2514SUL (1 g ETX2514, 1 g sulbactam) administered as a 3-h i.v. infusion every 6 h. Lines represent the median concentrations. Shaded regions represent the 3-h infusion period. The y axes are log scale.

FIG 3

Individual concentrations of sulbactam in plasma, epithelial lining fluid (ELF), and alveolar macrophages (AM) at the BAL fluid sampling times after the third dose of ETX2514SUL (1 g ETX2514, 1 g sulbactam) administered as a 3-h i.v. infusion every 6 h. Lines represent the median concentrations. Shaded regions represents the 3-h infusion period. The y axes are log scale.

FIG 4

Mean (± SD) plasma (black circles), epithelial lining fluid (ELF) (white triangles), and alveolar macrophages (AM) (gray squares) concentrations of ETX2514 (A) and sulbactam (B) at the BAL fluid sampling times after the third dose of ETX2514SUL (1 g ETX2514, 1 g sulbactam) administered as a 3-h i.v. infusion every 6 h. Shaded regions represent the 3-h infusion period. The y axes are log scale.