Lack of effect of gemifloxacin on the steady-state pharmacodynamics of warfarin in healthy volunteers

Gemifloxacin is a novel fluoroquinolone with a broad spectrum of activity. This double-blind, randomized, parallel-group study was designed to demonstrate the lack of effect of steady-state concentrations of gemifloxacin on the pharmacodynamic effects of warfarin. Healthy male subjects received loading doses of warfarin on days 1 and 2. The warfarin dose was freely titrated until day 10, with the aim of achieving a stable international normalized ratio (INR) for prothrombin time within the range 1.3-1.8 by day 14. On days 14-24 the dose of warfarin was fixed. On days 18-24, subjects also received 320 mg of gemifloxacin or matched placebo, once daily. Thirty-five subjects entered into and completed the co-administration phase of the study. The mean (standard deviation) baseline INR (mean of days 16-18) and INR for day 24 for gemifloxacin plus warfarin were 1.52 (0.12) and 1.46 (0.15), respectively. Corresponding values for placebo plus warfarin were 1. 46 (0.11) and 1.42 (0.17). The point estimate (90% confidence interval) for the difference in day 24 INR, adjusted for baseline, between gemifloxacin and placebo was 0.02 (-0.08, 0.12), which translates to an INR (relative to placebo least squares mean of 1.43) of 1.02 (0.95, 1.09). The 90% confidence interval for the difference in INR between the gemifloxacin and placebo groups was completely contained within the 25% equivalence range. There were no changes of clinical significance in vital signs, 12-lead electrocardiogram readings or laboratory parameters for any subject during the co-administration phase of the study, and no adverse experiences relating to coagulation were reported during this period. It is concluded that the pharmacodynamic effects of warfarin are not affected by gemifloxacin, and therefore both drugs can be co-administered without dosage adjustment.