Comparison of Plasma and Intrapulmonary Concentrations of Nafithromycin (WCK 4873) in Healthy Adult Subjects

Abstract

The nafithromycin concentrations in the plasma, epithelial lining fluid (ELF), and alveolar macrophages (AM) of 37 healthy adult subjects were measured following repeated dosing of oral nafithromycin at 800 mg once daily for 3 days. The values of noncompartmental pharmacokinetic (PK) parameters were determined from serial plasma samples collected over a 24-h interval following the first and third oral doses. Each subject underwent one standardized bronchoscopy with bronchoalveolar lavage (BAL) at 3, 6, 9, 12, 24, or 48 h after the third dose of nafithromycin. The mean ± standard deviation values of the plasma PK parameters after the first and third doses included maximum plasma concentrations (Cmax) of 1.02 ± 0.31 μg/ml and 1.39 ± 0.36 μg/ml, respectively; times to Cmax of 3.97 ± 1.30 h and 3.69 ± 1.28 h, respectively; clearances of 67.3 ± 21.3 liters/h and 52.4 ± 18.5 liters/h, respectively, and elimination half-lives of 7.7 ± 1.1 h and 9.1 ± 1.7 h, respectively. The values of the area under the plasma concentration-time curve (AUC) from time zero to 24 h postdosing (AUC0-24) for nafithromycin based on the mean or median total plasma concentrations at BAL fluid sampling times were 16.2 μg · h/ml. For ELF, the respective AUC0-24 values based on the mean and median concentrations were 224.1 and 176.3 μg · h/ml, whereas for AM, the respective AUC0-24 values were 8,538 and 5,894 μg · h/ml. Penetration ratios based on ELF and total plasma AUC0-24 values based on the mean and median concentrations were 13.8 and 10.9, respectively, whereas the ratios of the AM to total plasma concentrations based on the mean and median concentrations were 527 and 364, respectively. The sustained ELF and AM concentrations for 48 h after the third dose suggest that nafithromycin has the potential to be a useful agent for the treatment of lower respiratory tract infections. (This study has been registered at ClinicalTrials.gov under registration no. NCT02453529.).

Keywords: alveolar macrophages; epithelial lining fluid; nafithromycin; pharmacokinetics.

Copyright © 2017 American Society for Microbiology.

Figures

FIG 1

Mean ± SD plasma concentration-versus-time profile of nafithromycin before and in the 24-h interval following the first (A) and third (B) oral doses of 800 mg once daily.

FIG 2

Individual concentrations of nafithromycin in plasma (circles), epithelial lining fluid (ELF; triangles), and alveolar macrophages (AM; squares) at 3, 6, 9, 12, 24, and 48 h after the third oral dose of 800 mg once daily. The data on the y axis are on the log scale.

FIG 3

Mean ± SD concentration-versus-time profiles of nafithromycin in plasma, epithelial lining fluid (ELF), and alveolar macrophages (AM) at 3, 6, 9, 12, 24, and 48 h after the third oral dose of 800 mg once daily. The data on the y axis are on the log scale.