Intrapulmonary Pharmacokinetics of Levonadifloxacin following Oral Administration of Alalevonadifloxacin to Healthy Adult Subjects

Abstract

Alalevonadifloxacin (WCK 2349) is a novel l-alanine ester prodrug of levonadifloxacin that is being developed as an oral fluoroquinolone antibiotic. The primary objective of this study was to determine and compare plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of levonadifloxacin following oral administration of alalevonadifloxacin to healthy adult subjects. Levonadifloxacin concentrations in plasma, ELF, and AM samples from 30 healthy subjects were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) following oral dosing of alalevonadifloxacin (1,000 mg twice daily for 5 days). Six subjects were assigned to each bronchoalveolar lavage (BAL) fluid sampling time, i.e., 2, 4, 6, 8, or 12 h after the ninth oral dose. Noncompartmental pharmacokinetic (PK) parameters were determined from serial total plasma concentrations collected over a 12-h interval following the first and ninth oral doses. Penetration ratios were calculated from the areas under the concentration-time curves from 0 to 12 h (AUC0-12) for plasma, ELF, and AM by using mean (and median) concentrations at each BAL sampling time. Unbound plasma concentrations (∼85% plasma protein binding) were used to determine site-to-plasma penetration ratios. Plasma PK parameter values for levonadifloxacin were similar after the first and ninth doses. The respective AUC0-12 values based on mean ELF and AM concentrations were 172.6 and 35.3 mg · h/liter, respectively. The penetration ratios for ELF and AM levonadifloxacin concentrations to unbound plasma levonadifloxacin concentrations were 7.66 and 1.58, respectively. Similar penetration ratios were observed with median concentrations. The observed plasma, ELF, and AM concentrations of levonadifloxacin support further studies of alalevonadifloxacin for treatment of lower respiratory tract bacterial infections caused by susceptible pathogens. (This study has been registered at ClinicalTrials.gov under identifier NCT02253342.).

Keywords: alalevonadifloxacin; alveolar macrophages; epithelial lining fluid; levonadifloxacin; pharmacokinetics.

Copyright © 2018 American Society for Microbiology.

Figures

FIG 1

Mean (±SD) plasma concentration-versus-time profiles of levonadifloxacin before and in the 12-h interval following the first (A) and ninth (B) oral doses of alalevonadifloxacin (1,000 mg every 12 h).

FIG 2

Individual concentrations of levonadifloxacin in plasma (total) (circles), epithelial lining fluid (ELF) (triangles), and alveolar macrophages (AM) (squares) 2, 4, 6, 8, and 12 h after the ninth oral dose of alalevonadifloxacin (1,000 mg every 12 h). The y axis is on the log scale.

FIG 3

Mean (±SD) concentration-versus-time profiles of levonadifloxacin in plasma (unbound) (circles), epithelial lining fluid (ELF) (triangles), and alveolar macrophages (AM) (squares) 2, 4, 6, 8, and 12 h after the ninth oral dose of alalevonadifloxacin (1,000 mg every 12 h). The y axis is on the log scale.