PHARMACOKINETICS OF GREPAFLOXACIN AFTER ORAL-ADMINISTRATION OF SINGLEAND REPEAT DOSES IN HEALTHY-YOUNG MALES

The pharmacokinetics of grepafloxacin in healthy male subjects followi ng single oral administration of doses ranging from 200 to 1200mg, and following repeated oral administration of 400 and 800mg doses are rep orted. Plasma levels of grepafloxacin reached a peak within 2 hours (o n average) following drug administration and then declined bi-exponent ially with concentrations being detectable (>5 mu g/L) in the plasma f or at least up to 72 hours postdose. The high values for the apparent volume of distribution (5 to 8 L/kg) suggested extensive distribution of grepafloxacin in the tissues. Only a small percentage of the admini stered dose (ranging from 6% to 9.5%) was recovered in the urine as un changed grepafloxacin, suggesting that metabolism, rather than urinary excretion, is the major elimination route. The half-life of grepaflox acin was about 12 hours after single doses and about 15 hours after re peat doses. The trough levels increased significantly over the first 3 days of repeat administration; thereafter, the changes were small, wi th steady-state being reached by the fifth day. The area under the con centration-time curve (AUC(24h)) values observed on days 7 and 14 of r epeat administration, at each dose level, were similar, suggesting tha t steady-state is maintained. The area values increased more than prop ortionally after administration of increasing single and repeat doses, suggesting nonlinear kinetics. The elimination half-life and renal cl earance did not change with increasing doses. Saturation in the metabo lism of grepafloxacin and possibly in the distribution into a peripher al compartment, as suggested by a decrease in the total plasma clearan ce and in the apparent volume of distribution, could be the origin of the nonlinear kinetics. However, this deviation from linearity is unli kely to be of clinical significance, since it was very small over the recommended range of therapeutic doses (400 to 600mg once daily). Comp ared with other quinolones, grepafloxacin showed the longest half-life and the highest apparent volume of distribution. These features, toge ther with the excellent bactericidal activity of grepafloxacin, suppor t the recommended dosage regimen of grepafloxacin for the treatment of respiratory tract infections and sexually transmitted diseases.