Safety and pharmacokinetics of a single oral dose of gatifloxacin in patients with moderate to severe hepatic impairment.

Abstract

To assess the safety and pharmacokinetics of oral gatifloxacin 400 mg in subjects with and without hepatic impairment, and the need to modify doses in patients with hepatic dysfunction. Single-dose, nonrandomized, open-label, parallel-group study. Clinical Research Center, New Orleans, Louisiana. Eight subjects with grade B or C hepatic dysfunction (Child-Pugh classification) and eight age-, weight-, and gender-matched subjects with normal hepatic function. After a single oral dose of gatifloxacin 400 mg, blood and urine samples were collected at specified times or intervals over 48 hours to determine drug concentrations. All 16 subjects (7 with grade B and 1 with grade C hepatic impairment, 8 with normal hepatic function) completed the study. Peak plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0-infinity) for gatifloxacin were 32% and 22% higher, respectively, in subjects with hepatic impairment. Except for Cmax, the ratio of means for AUC satisfied the specified criterion (0.67-1.50) for lack of effect. There were no statistically significant differences in any other pharmacokinetic values except apparent oral clearance (ClT/F). All treatment-emergent adverse events were mild or moderate in intensity and resolved before subjects were discharged from the study. Modest increases in Cmax and AUC0-infinity are not anticipated to have a negative effect on the outcome of therapy in hepatically impaired subjects, nor are they anticipated to result in adverse drug reactions. Patients with moderate to severe (Child-Pugh grade B or C) hepatic dysfunction do not require gatifloxacin dose adjustments. In addition, the similarity in half-life (t1/2) for the groups (8.9 hrs for hepatically impaired subjects, 9.3 hrs for controls) suggests that no difference would be anticipated in the extent of drug accumulation after multiple doses. The overall safety and tolerability of a single oral dose of gatifloxacin 400 mg were excellent in both healthy subjects and those with hepatic impairment.