Pharmacokinetics and dose proportionality of ketoconazole in normal volunteers

Ketoconazole is an orally effective, broad-spectrum, systemic antifungal agent. The pharmacokinetics and bioavailability of ketoconazole given as a 200-mg single dose in a tablet, suspension, or solution were studied in 24 fasting healthy males by using a crossover design. Levels of ketoconazole in plasma were determined for up to 48 h by a sensitive reverse-phase high-performance liquid chromatography method. The absorption of ketoconazole was rapid, with mean maximum concentrations of the drug in plasma of 4.2, 5.0, and 6.2 micrograms/ml attained at 1.7, 1.2, and 1.0 h, respectively, after administration of the tablet, suspension, and solution, respectively. The mean distribution and elimination half-life values were 1.5 to 1.7 and 7.5 to 7.9 h, respectively. The mean oral clearance of the solution dose was 209 (+/- 82.9 [standard deviation]) ml/min, and the mean apparent volume of distribution was 88.31 (+/- 68.72) liters. The relative bioavailabilities for the tablet and suspension were 81.2 (+/- 33.5) and 89.0 (+/- 23.1)%, respectively, of that of the solution. The data indicated the bioequivalence of the tablet to the suspension and of the suspension of the solution. Dose proportionality of ketoconazole was also studied in 12 volunteers after they received solution doses of 200, 400, and 800 mg. Linear correlations between the dose and the maximum concentration of the drug in plasma, the time to the maximum concentration, and the area under the concentration-time curve were observed. However, the increase in the area under the curve was more than proportional to the dose given. The levels in plasma seemed to decay at a lower rate after 400- and 800-mg doses. The mean oral clearance decreased from 244.9 to 123.6 and 80.0 ml/min, respectively, as the dose increased from 200 to 400 and 800 mg. The apparent dose-dependent kinetics may have been due to the presystemic elimination and capacity-limited hepatic metabolism which become saturated at higher doses.