PHARMACOKINETICS OF FLEROXACIN AFTER MULTIPLE ORAL DOSING IN PATIENTSRECEIVING REGULAR HEMODIALYSIS

The pharmacokinetic profile of fleroxacin was studied in eight noninfe cted patients receiving regular hemodialysis (four women and four men; mean age, 63 Sears; age range, 48 to 73 years), Dialysis clearances ( mean +/- standard deviation) calculated from the amount of drug recove red in the dialysate exceeded those calculated from rates of extractio n from plasma for fleroxacin (126 +/- 29 versus 73 +/- 11 ml/min) and its metabolite N-demethylfleroxacin (103 +/- 31 versus 72 +/- 15 ml/mi n) but not that for the metabolite fleroxacin N-oxide (100 +/- 26 vers us 100 +/- 12 ml/min), Data were fitted to a two-compartment model ove r the total observation period of 8 days (six oral daily doses of 200 mg of fleroxacin on days 1 to 6 and hemodialysis treatments on day 1, 3, and 6) by nonlinear mixed-effects modeling, The random variability of plasma fleroxacin concentrations was 13% about its prediction, The estimated metabolic clearance was 25 ml/min (coefficient of variation, 43%), and the calculated steady-state volume of distribution was 84 l iters (coefficient of variation, 16%). The model was expanded for the two major metabolites by the addition of a two-compartment metabolite distribution, Formation clearances of N-demethylfleroxacin and fleroxa cin N-oxide were estimated to be 54 and 33% of fleroxacin's metabolic clearance, respectively. The conclusions were as follows, Because of t he slow metabolic clearance and intermittent dialysis treatment, stead y-state conditions were not reached after I week of oral fleroxacin th erapy, and there was relevant accumulation of fleroxacin as well as th at of fleroxacin N-oxide in our patients with end-stage renal disease. We recommend that infected hemodialysis patients be treated with an i nitial oral dose of 400 mg of fleroxacin and then daily oral doses of 200 mg, One cannot recommend the treatment of this patient population with fleroxacin over prolonged time periods until more data about the levels of accumulation of fleroxacin and its metabolites in infected p atients with renal disease are available.