Multiple-Dose Safety and Pharmacokinetics of Oral Garenoxacin in Healthy Subjects

Abstract

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.

Efficacy of Garenoxacin in Treatment of Experimental Endocarditis Due to Staphylococcus aureus or Viridans Group Streptococci

“…The peak (1 h) and trough (24 h) concentrations (mean Ϯ standard deviation for 9 to 15 individual animals for each drug) were (i) 6.1 Ϯ 0.9 and 1.0 Ϯ 0.6 mg/liter, respectively, for garenoxacin and (ii) 7.3 Ϯ 0.2 and 1.5 Ϯ 0.4 mg/liter, respectively for levofloxacin. The AUC 0-24 s for garenoxacin and levofloxacin were 63.4 and 55.6 mg ⅐ h/liter, respectively, i.e., very close to the values reported for these drugs in humans (7,8,21; Stewart et al, 41st ICAAC). The levels of intravegetation penetration of garenoxacin, expressed as the percentage of the drug concentration measured in the vegetation compared to the concentration measured in the serum of four individual animals, were 59% (range, 56 to 62%) at the peak concentration and 67% (range, 53 to 69%) at the trough concentration.…”

Mutant Selection Window Hypothesis Updated

“…However, determination of MPC with ciprofloxacin-resistant isolates indicates that garenoxacin resistance would be acquired as quickly as ciprofloxacin resistance by fully susceptible isolates [60,61]; in both cases, serum drug concentrations are within the selection window for much of the dosing period [62]. These same in vitro measurements indicate that garenoxacin trials with ciprofloxacin-susceptible isolates might be successful if drug concentrations at the site of mutant amplification are at least as high as serum concentrations (i.e., serum drug concentrations are above MPC for the entire dosing period) [62,63].…”

Activities of Different Fluoroquinolones against Bacillus anthracis Mutants Selected In Vitro and Harboring Topoisomerase Mutations

“…They were 2-to 8-fold and 4-to 16-fold lower than those observed for gatifloxacin and moxifloxacin, respectively. Thus, the mutants would be within the suceptibility range for garenoxacin, in contrast to most of the quinolones tested (9). It was previously shown that garenoxacin was very active against gram-positive organisms and, in particular, was still active against some strains of S. aureus and S. pneumoniae harboring mutations in both the topoisomerase IV and the gyrase (6,12,13).…”