No abstract

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.

Max word count; current word count: 4000; 3988No. tables/figures: 5 (3 tables, 2 figures) Principal Investigator statementThe authors confirm that the PI for this paper is Dave Singh and that he had direct clinical responsibility for patients. Data availability statementAnonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com. The trial protocol is available at https://www.gsk-studyregister.com/en/ Funding sources and roleThis study was funded by GlaxoSmithKline (GSK ID 205722; NCT03287310) Authors contributionsAll authors reviewed and revised the manuscript, approved the final version, and made the decision to submit the manuscript for publication. Additionally, SM, IJP and NPB were involved in the conception and design of the study, DS and RF were involved in the acquisition of the data, and IJP, KH, YLM, NPB, SWY and AC were involved in the data analysis and interpretation.

Gemifloxacin is a novel fluoroquinolone, currently in development for the treatment of respiratory tract infections. This double-blind (with respect to gemifloxacin), randomized, crossover study investigated the possibility of pharmacokinetic interaction between gemifloxacin and theophylline. After a 4–8-day run-in phase to establish the dose of theophylline required to achieve a trough plasma concentration range of 8–15 mg/l, 15 healthy volunteers entered a randomized treatment phase. Volunteers then received oral theophylline, 300–400 mg twice daily, for 22 days. On days 5–11 and 16–22, they also received either placebo or gemifloxacin, 320 mg p.o. once daily, in a crossover fashion. Blood samples were collected up to 12 h after the morning dose of theophylline on days 11 and 22. Theophylline pharmacokinetics were not affected by the co-administration of gemifloxacin. The maximum plasma concentration (C_max) for theophylline ranged from 8.12 to 17.71 mg/l and from 8.79 to 16.35 mg/l during concomitant administration with gemifloxacin and placebo, respectively. The corresponding ranges of the area under the plasma concentration-time curve from time zero to the last quantifiable plasma concentration (AUC_(0–12)) were 84.6–177.5 mg·h/l and 94.8–165.1 mg·h/l during gemifloxacin and placebo administration, respectively. The point estimates (90% confidence intervals) for dose-normalized AUC_(0–12) and C_max (theophylline + gemifloxacin):(theophylline + placebo) were 0.99 (0.93, 1.05) and 1.02 (0.93, 1.11), respectively, which were entirely within the equivalence range (0.80, 1.25). The co-administration of gemifloxacin and theophylline was well tolerated, with no clinically significant changes seen in vital signs, 12-lead electrocardiogram readings or laboratory parameters. Adverse events were generally transient, mild to moderate in nature and similar during the gemifloxacin and placebo treatment periods. In conclusion, theophylline and gemifloxacin may be co-administered without any adjustment in theophylline dose.

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.