Intrapulmonary Pharmacokinetics of Levonadifloxacin Following Oral Administration of Alalevonadifloxacin to Healthy Adult Subjects [PublishAheadOfPrint]

Alalevonadifloxacin (WCK 2349) is a novel L-alanine ester prodrug of levonadifloxacin 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 in healthy adult subjects. Levonadifloxacin concentrations in plasma, ELF, and AM of 30 healthy subjects were measured by LC-MS/MS following oral dosing of alalevonadifloxacin (1000 mg twice daily for 5 days). Six subjects were assigned to each bronchoalveolar lavage sampling time at 2, 4, 6, 8 or 12 hours after the ninth oral dose. Noncompartmental pharmacokinetic (PK) parameters were determined from serial total plasma concentrations collected over a 12-hour interval following the first and ninth oral doses. Penetration ratios were calculated from the AUC_0—12 for plasma, ELF, and AM using mean (and median) concentrations at each BAL sampling times. Unbound plasma concentrations (plasma protein binding ~85%) 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 AUC_0-12 values based on mean ELF and AM concentrations were 172.6 and 35.3 mg·h/L, respectively. The penetration ratios for ELF and AM 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.

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