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

Nafithromycin concentrations in plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) of 37 healthy adult subjects were measured following repeated dosing of oral nafithromycin 800 mg once daily for three days. Noncompartmental pharmacokinetic (PK) parameters were determined from serial plasma samples collected over a 24-hour 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 hours after the third dose of nafithromycin. Mean (± SD) plasma PK parameters after the first and third dose included C_max of 1.02 ± 0.31 and 1.39 ± 0.36 μg/mL, t_max of 3.97 ± 1.30 h and 3.69 ± 1.28 h, CL/F of 67.3 ± 21.3 L/h and 52.4 ± 18.5 L/h, and elimination t1/2 of 7.7 ± 1.1 and 9.1 ± 1.7 h. AUC_0-24 values of nafithromycin based on mean or median total plasma concentrations at BAL sampling times were 16.2 μg·h/mL. For ELF, the respective AUC_0-24 values based on mean and median concentrations were 224.1 and 176.3 μg·h/mL, whereas AUC_0-24 values for AM were 8538 and 5894 μg·hr/mL. Penetration ratios based on ELF and total plasma AUC_0-24 values based on mean and median concentrations were 13.8 and 10.9, whereas ratios of AM to total plasma concentrations were 527 and 364. The sustained ELF and AM concentrations for 48 hours after the third dose suggest that nafithromycin has the potential to be a useful agent for the treatment of lower respiratory tract infections.

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