PHARMACOKINETICS, SAFETY, AND TOLERABILITY OF FLOSEQUINAN IN PATIENTS WITH HEPATIC-DYSFUNCTION

The pharmacokinetics of flosequinan and its active metabolite, flosequinoxan, were investigated following a single 100-mg oral dose in 10 patients with compromised hepatic function. Plasma and urine samples were collected for up to 144 h postdose and analyzed by HPLC. All 10 patients provided analyzable data even though one patient withdrew before the 144-h sample because of an adverse event unrelated to the study medication. Interpatient variability was appreciable for the plasma and urine concentrations was well as for the calculated pharmacokinetic parameters. Relative to a comparative cohort of normal subjects, flosequinan concentrations in the study patients were elevated, showing increases in mean AUC(0-t) (62.8 +/- 49.4 vs 3.4 +/- 1.5 mu g.h/mL), AUC(0-infinity) (70.2 +/- 58.3 vs 3.8 +/- 1.6 mu g.h/mL), C-max (2.43 +/- 0.56 vs 1.30 +/- 0.39 mu g/mL), and t(1/2) (20.7 +/- 16.8 vs 1.7 +/- 0.5 h). The mean systemic clearance decreased (47.3 +/- 46.5 vs 544 +/- 279 mL/min), along with the elimination rate constant (0.066 +/- 0.069 vs 0.44 +/- 0.13 h(-1)). Mean flosequinoxan AUC(0-t) and AUC(0-infinity) values were unaffected by hepatic dysfunction. The mean time to peak was longer (36.4 +/- 27.4 vs 7.0 +/- 3.1 h) and C-max was less (0.98 +/- 0.52 vs 1.84 +/- 0.26 mu g/mL) than in normal subjects. These findings are consistent with a decrease in the rate of flosequinan metabolism to flosequinoxan. Five patients reported adverse events, which included headache (three patients) and syncope (one patient). Thus the consequences of hepatic dysfunction are a longer flosequinan elimination time, resulting in elevated flosequinan plasma levels, and a decrease in the rate flosequinoxan formation. This decrease in metabolic rate leads to an increased exposure to total quinolones (72% more) for patients with hepatic dysfunction than for normal subjects. On the basis of the results of this study, it is suggested that dosage adjustment should be considered in patients with hepatic dysfunction.