Assessment of electrocardiograms and garenoxacin plasma concentrations from subjects with acute bacterial infections

Abstract number: 1733_1516

Krishna G., Waskin H.

Background: Treatment with certain fluoroquinolones may increase the risk of QT interval (QT) prolongation. Garenoxacin is a novel des-F(6)-quinolone with broad antimicrobial activity against clinically important pathogens including multidrug-resistant S. pneumoniae. The relationship between maximal plasma garenoxacin concentration (Cmax) and QT measurements has been studied in Phase I studies in healthy (predominantly young male) subjects but not in subjects treated with IV garenoxacin for an acute bacterial infection. This analysis assessed for possible correlation between peak plasma garenoxacin values and QT abnormalities in subject populations that included women, elderly, and those with underlying electrolyte disturbances.

Methods: Following informed consent, electrocardiographs (ECG) and plasma samples were collected from subjects enrolled in 5 randomised, comparative, multicentre, double-blind, Phase 3 studies of IV garenoxacin (400 mg or 600 mg once daily). Serial ECG data and blood samples were collected before the first dose of study medication on day 1 (baseline), within 3 h after the end of the first infusion, and once on study day 3, 4, or 5. For this analysis, only data from the garenoxacin cohorts (unblinded after data lock) are presented. Blood samples (5 mL) were collected immediately following ECG measurements. For this retrospective analysis, the potential association between changes in ECG parameters from baseline to post-dose, measured as maximal QTcF interval at anticipated Cmax, and plasma garenoxacin concentration was examined using linear regression analysis.

Results: Collectively, 800 subjects (52%/48% M/F, 24% ≥65 yr old) received garenoxacin treatment. No association was apparent between maximum QTcF and garenoxacin plasma concentrations ranging from 0 to >20 mg/mL. These results were consistent with data from a previous analysis of QTc versus garenoxacin concentration in Phase I studies. There were no trends in interval abnormalities or change from baseline of ≥60 ms in the various garenoxacin concentration strata, including the highest concentration stratum (>20 mg/mL). Similarly, no statistically significant temporal change in QTc from baseline was observed after the first dose of garenoxacin or after 3 to 5 days of treatment.

Conclusion: Garenoxacin does not demonstrate clinically significant concentration- or time-dependent effects on QT intervals in subjects receiving IV treatment for acute bacterial infections.