Safety, Tolerability, And Pharmacokinetics Of Oral Nafithromycin (Wck 4873) After Single Or Multiple Doses And Effects Of Food On Single-Dose Bioavailability In Healthy Adult Subjects

Nafithromycin (WCK 4873), a novel lactone-ketolide, was administered to healthy adult subjects in 2 randomized, double-blind, placebo-controlled, phase 1 studies. In the first-in-human study, single ascending oral doses of nafithromycin (100 to 1,200 mg) were administered to subjects under fasted or fed conditions, with effects of food on bioavailability of nafithromycin studied at the dose levels of 400 and 800 mg. In the second study, multiple ascending oral doses of 600, 800, or 1,000 mg of nafithromycin were administered once daily for 7 days under fed conditions. Nafithromycin was generally well tolerated at all doses. No serious or severe adverse events were observed. The mean maximum plasma concentration (C-max) ranged from 0.099 to 1.742 mg/liter, and the area under the concentration-time curve from time zero to time t (AUC(0-t)) ranged from 0.54 to 22.53 h.mg/liter. Nafithromycin plasma AUC(0-t) increased approximately 1.2-fold under fed compared to fasted conditions. In the multiple-dose study, the day 7 nafithromycin C-max ranged from 1.340 to 2.987 mg/liter and the AUC over the final dosing interval (AUC(0-t)) ranged from 13.48 to 43.46 h.mg/liter . The steady state was achieved after 3 days for the 600-mg and 800-mg-dose cohorts and after 4 days for the 1,000-mg cohort. Under both single- and multiple-dosing regimens, plasma exposure to nafithromycin appeared to increase more than dose proportionally. Nafithromycin showed moderate accumulation on day 7 of dosing. The human pharmacokinetic profile, safety, and tolerability data support further development of nafithromycin.