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.

Garenoxacin (T-3811ME, BMS-284756) is a novel des-F(6) quinolone that has been shown to be effective in vitro against a wide range of clinically important pathogens, including gram-positive and gram-negative aerobes and anaerobes. This study was conducted to evaluate the safety and tolerability of multiple oral doses (100 to 1,200 mg/day) of garenoxacin in healthy subjects and to determine its multiple-dose pharmacokinetics. Forty healthy male and female subjects (18 to 45 years of age) were enrolled in this randomized, double-blind, placebo-controlled, sequential, multiple-and ascending-dose study. Each subject received a once-daily oral dose of garenoxacin (100, 200, 400, 800, or 1,200 mg) or a placebo for 14 days. Blood and urine samples were collected for measurements of garenoxacin by validated liquid chromatography with dual mass spectrometry, and plasma garenoxacin concentration-time data were analyzed by noncompartmental methods. The effects of garenoxacin on Helicobacter pylori, psychometric test performance, and electrocardiograms were assessed, as was drug safety. Over the 14 days of dosing, geometric mean peak concentrations of garenoxacin in plasma (C max ) at the 100-and 1,200-mg doses were within the ranges of 1.2 to 1.6 and 16.3 to 24 g/ml, respectively. The corresponding values for the geometric mean area under the concentration-time curve over the dosing interval (AUC ) for garenoxacin in plasma at the 100-and 1,200-mg doses were within the ranges of 11.5 to 15.7 and 180 to 307 g ⅐ h/ml, respectively. Increases in systemic exposure to garenoxacin in terms of AUC and C max were approximately dose proportional over the 100-to 400-mg dose range but demonstrated increases that were somewhat greater than the dose increments at the 800-and 1,200-mg doses. Median values for the time to achieve C max were in the range of 1.13 to 2.50 h for all doses. The mean elimination half-life for garenoxacin in plasma appeared to be independent of dose and ranged from 13.3 to 17.8 h (day 14). Approximately 30 to 50% of an administered garenoxacin dose was excreted unchanged in the urine. At doses of 100 to 400 mg, steady-state concentrations of garenoxacin in plasma appeared to be attained by the fourth dose. Multiple oral doses of garenoxacin were well tolerated and did not demonstrate clinically significant effects on QT c or psychometric test results. Garenoxacin administered alone for 14 days at doses of >400 mg demonstrated activity against H. pylori. These results suggest that multiple once-daily oral doses of garenoxacin of up to 1,200 mg are safe and well tolerated and that the pharmacokinetics of garenoxacin support once-daily administration.

Gatifloxacin was well tolerated in patients with NIDDM controlled by diet and exercise. It had no significant effect on glucose homeostasis, beta-cell function, or long-term fasting serum glucose levels, but it did cause a brief increase in serum insulin levels.

Garenoxacin (T-3811ME, BMS-284756) is a novel, broad-spectrum des-F(6) quinolone currently under study for the treatment of community-acquired respiratory tract infections. This analysis assessed garenoxacin population pharmacokinetics and exposure-response relationships for safety (adverse effects [AE]) and antimicrobial activity (clinical cure and bacteriologic eradication of Streptococcus pneumoniae and the grouping of Haemophilus influenzae, Haemophilus parainfluenzae, and Moraxella catarrhalis). Data were obtained from three phase II clinical trials of garenoxacin administered orally as 400 mg once daily for 5 to 10 days for the treatment of community-acquired pneumonia, acute exacerbation of chronic bronchitis, and sinusitis. Samples were taken from each patient before drug administration, 2 h following administration of the first dose, and on the day 3 to 5 visit. Individual Bayesian estimates of the fu (fraction unbound), the C max , and the fu for the area under the concentration-time curve from 0 to 24 h (fu AUC 0-24 ) were calculated as measurements of drug exposure by using an ex vivo assessment of average protein binding. Regression analysis was performed to examine the following relationships: treatment-emergent AE incidence and AUC 0-24 , C max , or patient factors; clinical response or bacterial eradication and drug exposure (fu C max /MIC, fu AUC 0-24 /MIC, and other exposure covariates); or disease and patient factors. Garenoxacin pharmacokinetics were described by a one-compartment model with first-order absorption and elimination. Clearance was dependent on creatinine clearance, ideal body weight, age, obesity, and concomitant use of pseudoephedrine. The volume of distribution was dependent on weight and gender. Patients with mild or moderate renal dysfunction had, on average, approximately a 16 or 26% decrease in clearance, respectively, compared to patients of the same gender and obesity classification with normal renal function. AE occurrence was not related to garenoxacin exposure. Overall, clinical cure and bacterial eradication rates were 91 and 90%, respectively, for S. pneumoniae and 93 and 92%, respectively, for the grouping of H. influenzae, H. parainfluenzae, and M. catarrhalis. The fu AUC 0-24 /MIC ratios were high (>90% were >200), and none of the pharmacokinetic-pharmacodynamic exposure measurements indexed to the MIC or other factors were significant predictors of clinical or bacteriologic response. Garenoxacin clearance was primarily related to creatinine clearance and ideal body weight. Although garenoxacin exposure was approximately 25% higher for patients with moderate renal dysfunction, this increase does not appear to be clinically significant as exposures in this patient population were not significant predictors of AE occurrence. Garenoxacin exposures were at the upper end of the exposure-response curves for measurements of antimicrobial activity, suggesting that 400 mg of garenoxacin once daily is a safe and adequate dose for the treatment of the specified community-ac...

Based on the broad therapeutic index of garenoxacin, the effects of renal impairment on garenoxacin exposure are not considered clinically significant. There was a modest increase in AUC in subjects with severe renal impairment and the magnitude of the changes was not considered clinically relevant.