Pharmacokinetics of fluconazole in renal failure

Fluconazole (FLU) is a widely used antifungal agent. The multiple-dose pharmacokinetics of FLU in renal impairment have not been previously investigated. The following groups were studied: volunteers with creatinine clearances (CLcr, >50 mL/min) of 107 mL/min, given a loading dose of 400 mg and a daily dose of 200 mg/day for 9 days (Group 1); subjects with CLcr between 21 and 50 mL/min with a mean of 38 mL/min, given a loading dose of 200 mg and a maintenance dose of 100 mg/day for 9 days (Group 2); subjects with CLcr between 11 and 20 mL/min with a mean of 14.8 ml/min, given a loading dose of 100 mg and a maintenance dose of 50 mg/day for 9 days (Group 3); and subjects on hemodialysis (three times per week) receiving a loading dose of 200 mg and then 100 mg after each of four dialysis sessions (Group 4) (N = 10 per goup). After the administration of the loading dose on Day 1, the mean area under the curve (AUC) (0-24) measurements were approximately proportional to the dose of FLU and independent of renal function. After 10 days of FLU dosing, the mean renal clearance of FLU decreased as CLcr decreased for Group 1 to 3, and the Day 10 mean half-lives were inversely related to mean CLcr (36.7 h in Group 1, 84.5 h in Group 2 and 101.9 in Group 3). The mean AUC (0-24) on Day 10 was similar for Group 1 compared with Group 2, despite a reduction in the maintenance dose by 50%. The mean AUC (0-24) for Group 3, for which the maintenance dose was 25% of that for Group 1, decreased by approximately 50% as compared with Group 1. For subjects in Group 4, for which the maintenance dose was 50% of that for Group 1, hemodialysis resulted in a decrease in pre-dose serum concentrations of approximately 50% compared with Group 1. It was concluded that the loading dose for FLU need not be adjusted for the degree of renal impairment. The maintenance dose should be reduced by 50% for subjects with CLcr ≤50 mL/min, with no further reductions for subjects with Clcr <20 mL/min. Subjects on hemodialysis should receive the recommended maintenance dose after each hemodialysis session.