PHARMACOKINETICS OF THE TRIAZOLE ANTIFUNGAL AGENT GENACONAZOLE IN HEALTHY-MEN AFTER ORAL AND INTRAVENOUS ADMINISTRATION

The pharmacokinetics of genaconazole, a potent new difluorophenyl-tria zole antifungal agent, was studied in 12 healthy male volunteers follo wing a single oral or intravenous administration of the drug. In a ran domized two-way crossover design, each volunteer received either two 5 0-mg genaconazole tablets orally or a parenteral preparation containin g 100 mg of genaconazole given as a 30-min intravenous infusion. Both dosage regimens were well tolerated. Blood and urine samples were coll ected up to 10 days after drug administration. Concentrations of genac onazole in plasma and urine were determined by a specific highperforma nce liquid chromatography assay with a limit of quantitation of 0.1 mu g/ml. Pharmacokinetic evaluation following oral and intravenous doses indicated that mean values for the area under the concentration-time curve from 0 h to infinity (137 and 136 mu g .h/ml), half-life (50 and 49 h), volume of distribution (52 and 52 liters), and clearance (12 a nd 12 ml/min) were independent of the route of drug administration. Th e oral and intravenous administrations of genaconazole yielded virtual ly superimposable plasma concentration-time curves, resulting in an ab solute bioavailability of 100%. Amounts of unchanged genaconazole foun d in urine samples from 0 to 240 h after oral and intravenous doses we re comparable, and urinary excretion accounted for 76 and 78% of the a dministered dose, respectively. Renal clearances for the two routes of administration were also similar, and renal clearance accounted for o ver 80% of the total body clearance. The 100% absolute bioavailability of genaconazole regardless of the route of administration provides gr eater dosing flexibility in various clinical settings than currently e xists.