Retrospective analysis of electrocardiographic changes after administration of oral or intravenous garenoxacin in five phase I, placebo-controlled studies in healthy volunteers.

Background: Certain fluoroquinolones and macrolide antibiotics have been associated with prolongation of the corrected QT (QTc) interval or QT dispersion, leading to cardiac arrhythmias. Garenoxacin is a des-F(6)-quinolone with broad-spectrum antimicrobial activity and a favorable pharmacokinetic/pharmacodynamic profile. Its effects on electrocardiographic (ECG) parameters in healthy volunteers have not been reported.

Objective: The cardiac safety profile of garenoxacin was further examined using data from healthy volunteers enrolled in 5 dose-ranging and comparative Phase I clinical studies.

Methods: This was a retrospective analysis of 5 randomized, double-blind, placebo-controlled studies in which 224 healthy volunteers received oral or intravenous garenoxacin (50-1200 mg/d) for 1 to 28 days' dosing duration (
Results: No clinically relevant changes in the QTc or PR intervals were observed over a range of garenoxacin plasma concentrations (Cmax: 0.5-38.6 microg/mL, oral dose range; 3.36-21.4 microg/mL, intravenous dose range). No volunteer had a prolongation from baseline that exceeded established thresholds for the QTcB or QTcF interval (>450 milliseconds for men, >470 milliseconds for women) or the PR interval (>250 milliseconds). One subject had a change in QTcB of 67 milliseconds 4 hours after administration of garenoxacin 400 mg PO on day 7, but the actual value was 418 milliseconds (baseline, 351 milliseconds); the corresponding change in QTcF was 49 milliseconds (actual, 408 milliseconds; baseline, 359 milliseconds). The means for other derived ECG parameters were generally similar between garenoxacin-treated volunteers and placebo controls.

Conclusion: In this retrospective analysis of data from healthy volunteers, garenoxacin had no clinically relevant dose-, route-of-administration-, or concentration-dependent effects on the QTc or PR interval across a dose range from 50 to 1200 mg/d.