Gemifloxacin mesylate (SB-265805-S, LB-20304a) is a potent, novel fluoroquinolone agent with a broad spectrum of antibacterial activity. The pharmacokinetics and tolerability of oral gemifloxacin were characterized in two parallel group studies in healthy male volunteers after doses of 160, 320, 480, and 640 mg once daily for 7 days. Multiple serum or plasma and urine samples were collected on days 1 and 7 and were analyzed for gemifloxacin by high-performance liquid chromatography (HPLC)-fluorescence (study 1) or HPLC-mass spectrometry (study 2). Safety assessments included vital signs, 12-lead electrocardiogram (ECG) readings, hematology, clinical chemistry, urinalysis, and adverse experience monitoring. Gemifloxacin was rapidly absorbed, with a time to maximum concentration of approximately 1 h after dosing followed by a biexponential decline in concentration. Generally, maximum concentration and area under the concentration-time curve (AUC) increased linearly with dose after either single or repeat doses. Mean ؎ standard deviation values of AUC 0-on day 7 were 4.92 ؎ 1.08, 9.06 ؎ 2.20, 12.2 ؎ 3.69, and 20.1 ؎ 3.67 g⅐h/ml following 160-, 320-, 480-, and 640-mg doses, respectively. The terminal-phase half-life was approximately 7 to 8 h, independent of dose, and was similar following single and repeated administrations. There was minimal accumulation of gemifloxacin after multiple dosing. Approximately 20 to 30% of the administered dose was excreted unchanged in the urine. The renal clearance was 160 ml/min on average after single and multiple doses, which was slightly greater than the accepted glomerular filtration rate (approximately 120 ml/min). These data show that the pharmacokinetics of gemifloxacin are linear and independent of dose. Gemifloxacin was generally well tolerated, although one subject was withdrawn from the study after 6 days at 640 mg for mild, transient elevations of alanine aminotransferase and aspartate aminotransferase not associated with any clinical signs or symptoms. There were no other significant changes in clinical chemistry, hematology or urinalysis parameters, vital signs, or ECG readings. In conclusion, the results of these studies, combined with the antibacterial spectrum and potency, support the further investigation of once-daily administration of gemifloxacin for indications such as respiratory tract and urinary tract infections.

This double-blind, randomized, parallel-group comparative study investigated the phototoxic potential of gemifloxacin mesylate, a potent, novel fluoroquinolone antimicrobial. Forty healthy male and female volunteers received repeat dosing for 7 days with 160 mg or 320 mg of gemifloxacin (o.d., p.m.), 500 mg of ciprofloxacin (b.d.) or placebo (b.d.). On day 5 (large step) and day 6 (small step), graded series of wavebands were irradiated onto the back of each volunteer (phototesting). Skin reactions were assessed 0–30 min (immediate erythema) and 24 and 48 h (delayed erythema) after irradiation. Both gemifloxacin, 320 mg o.d., and ciprofloxacin, 500 mg b.d., were associated with mild phototoxicity following 7 days of administration. The range of mean phototoxic indices (the ratio of minimal erythemal dose at baseline compared with that on day 7 at the end of dosing) was 1.00–2.19 for gemifloxacin and 0.97–2.23 for ciprofloxacin. The abnormal responses occurred within the ultraviolet A region (335–365 ± 30 nm) and were maximal at 24 h. Susceptibility to phototoxicity had cleared 48 h after stopping the drug. The phototoxicity observed with gemifloxacin, 160 mg o.d., was lower than that at the higher dose and similar to that of placebo, suggesting that gemifloxacin phototoxicity is dose dependent. There were no clinically important changes in the safety profiles of gemifloxacin and ciprofloxacin compared with placebo in healthy volunteers after 7 days of repeat dosing. This study demonstrated that gemifloxacin, 320 mg o.d. given for 7 days, has a low potential to cause mild photosensitivity which is similar to that of ciprofloxacin, 500 mg b.d., given for the same period.

This randomized, double-blind, 2-way crossover study investigated the effect of omeprazole on the pharmacokinetics of gemifloxacin, a novel fluoroquinolone. Thirteen healthy male volunteers received a 320 mg oral dose of gemifloxacin after 4 days of dosing with either omeprazole (40 mg once daily) or matching placebo. Blood was sampled for 48 h after dosing for determination of pharmacokinetic parameters. The mean area under the plasma concentration-time curve extrapolated to infinity (AUC_0–∞) and maximum plasma concentration (C_max) for gemifloxacin were increased by, on average, 10% (90% confidence interval [CI], 0.89, 1.36) and 11% (90% CI, 0.87, 1.43), respectively, when gemifloxacin was given after omeprazole compared with after placebo. Neither the time to C_max (T_max) nor the half-life of gemifloxacin appeared to be affected by administration of omeprazole. There were no clinically relevant changes in adverse events, vital signs or the results of laboratory investigations after co-administration of omeprazole compared with placebo. In view of the modest increase in systemic exposure and the likely maximal increases indicated by the CIs, the effect of omeprazole on gemifloxacin pharmacokinetics is not considered to be clinically significant. Gemifloxacin and omeprazole can therefore be co-administered with no requirement for a dose adjustment.

The effect of repeat oral doses of ritonavir, at high (600 mg twice daily) and low (100 mg twice daily) doses, on the pharmacokinetics of a single dose of bupropion was evaluated in healthy volunteers. Subjects received a single dose of 150 mg of bupropion on day 1 and twice-daily ritonavir from day 8 through day 30. Ritonavir was up-titrated from 300 mg twice daily to 600 mg twice daily in the high-dose ritonavir study, whereas subjects remained on 100 mg twice-daily ritonavir in low-dose ritonavir study. Subjects received a second single dose of bupropion on day 24. Serial blood samples were obtained to evaluate the pharmacokinetics of bupropion and its metabolites on days 1 and 24. Steady-state ritonavir led to a decrease of area under the curve and maximum plasma concentration of bupropion by 62% to 67% in the high-dose study and by 21% to 22% in the low-dose study, indicating a drug interaction of statistical and clinical significance, particularly at high doses of ritonavir. These studies demonstrate that the reduction of bupropion exposure by ritonavir is dose-related. Dosage adjustment of bupropion may be needed when administered with ritonavir. However, the maximum recommended daily dose of bupropion should not be exceeded.

This open, randomized, 4-way crossover study investigated the effect of the antacid Maalox^® on the bioavailability of gemifloxacin, a novel fluoroquinolone antimicrobial. Sixteen healthy male volunteers received gemifloxacin, 320 mg p.o., alone, 3 h after Maalox^® administration, or 10 min or 2 h before Maalox^® administration. Blood was sampled for 48 h after dosing to determine pharmacokinetic parameters. Estimates for the differences between regimens and 95% confidence intervals were calculated using the t-test for paired data. The administration of gemifloxacin 10 min before Maalox^® resulted in an average 85% reduction in the area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC_0–∞), whereas administration 3 h after Maalox^® produced a decrease in AUC_0–∞, 15% of which was not considered to be clinically significant. The administration of gemifloxacin 2 h before Maalox^® had no notable effect on the gemifloxacin AUC_0–∞ (average increase of 3%). Similar results were seen for the maximum gemifloxacin plasma concentration (C_max). Neither the time to C_max nor the half-life of gemifloxacin were notably altered by the administration of Maalox^® at any time relative to gemifloxacin dosing. There were no clinically important adverse experiences or changes in clinical laboratory parameters during this study. The findings of this study support the dosing recommendation that gemifloxacin can be administered either 2 h or more prior to, or 3 h or more after, the administration of Maalox^®.