A dose-escalation study of the safety, tolerability, and pharmacokinetics of intravenous gatifloxacin in healthy adult men

Study Objectives. To examine single- and multiple-dose safety, tolerability, and pharmacokinetics of gatifloxacin administered as daily 1-hour intravenous infusions for 14 days, and to determine the effect of gatifloxacin on glucose tolerance, pancreatic beta-cell function, and electrocardiogram (ECG). Design. Randomized, double-blind, placebo-controlled, ascending-dose study. Setting. Bristol-Myers Squibb, Clinical Pharmacology Unit, Princeton, New Jersey, USA. Patients. Forty healthy male subjects, eight in each of five groups, were enrolled to receive sequential doses of gatifloxacin: 200 mg (10 mg/ml), 200 mg (1 mg/ml), and 400, 600, and 800 mg (2 mg/ml); six subjects per group received active drug and two received placebo. Interventions. A single dose of the drug was administered as an intravenous infusion over 1 hour. After a 72-hour washout period, the drug was administered once/day for 14 days by 1-hour intravenous infusion. Physical examinations, ECGs, spirometry, and clinical laboratory tests, including glucose tolerance test (GTT) and assessment of glucose homeostasis, were performed before treatment and on selected dosing days. A safety evaluation was performed before escalating doses. No intrasubject dose escalation was permitted. Measurements and Main Results. The pharmacokinetics of gatifloxacin were dose linear and time independent after intravenous administration over the range of 200-800 mg. After daily repeated administration, a predictable, modest accumulation was observed; steady state was reached by the third dose. Approximately 80% of the dose was recovered as unchanged drug in urine. Mean changes (before the first dose to the last dose) after oral GTT and in fasting serum glucose, insulin, and C-peptide concentrations were comparable among the gatifloxacin and placebo treatment groups. A mild, transient decrease in serum glucose was associated with the end of the 1-hour infusion of gatifloxacin. No clinically important changes in QTc interval or spirometry occurred. The most frequent treatment-related adverse effects were local intravenous site reactions, which were associated with dose and/or concentration of intravenous solution. Conclusion. Gatifloxacin was safe and well tolerated at intravenous doses of up to 800 mg/day for 14 days. Gatifloxacin pharmacokinetics were linear and time independent.