Electrocardiographic Effects of a Supratherapeutic Dose of WCK 2349, a Benzoquinolizine Fluoroquinolone

Abstract

The purpose of this study was to measure the electrocardiographic (ECG) effects of WCK 2349 (the L‐alanine ester prodrug of levonadifloxacin) at a supratherapeutic oral dose of 2,600 mg. A total of 48 healthy volunteers were randomized to treatment with placebo, WCK 2349, or oral moxifloxacin, 400 mg, in a crossover‐designed thorough QT study. A supratherapeutic mean maximum levonadifloxacin concentration (Cmax) of 43.3 μg/mL was achieved at 3.1 hours. A therapeutic dose of 1,000 mg b.i.d. in a previous study in patients resulted in a Cmax of 17.8 μg/mL. WCK 2349 exerted no significant effect on baseline‐ and placebo‐corrected QTcF (QT interval corrected for heart rate (HR) by the Fridericia formula), QRS, or PR interval. HR was transiently accelerated by a maximum of 14.4 (95% confidence interval, 11.80–16.92) beats per minute (bpm) at 3 hours. Concentration–effect modeling predicted a mean increase of 8.0 bpm at Cmax at the standard therapeutic dose. A therapeutic dose of 1,000 mg b.i.d. of WCK 2349 is not expected to cause clinically significant ECG effects, except for a possible transient increase in HR, which seems to be clinically insignificant.