Pharmacokinetics of itraconazole and hydroxyitraconazole in healthy subjects after single and multiple doses of a novel formulation

Originally, itraconazole for parenteral administration was licensed in a 40% hydroxypropyl-beta-cyclodextrin (HPBCD) solution for intravenous administration. A novel formulation, the NanoCrystal formulation (NCF), was prepared. NCF consists of drug particles of approximately 200 to 300 nm. The pharmacokinetics of itraconazole and its hydroxy metabolite in healthy subjects were evaluated after single and multiple doses of itraconazole as NCF. In the single-ascending-dose (SAD) study, itraconazole doses were planned to range from 50 to 500 mg, while in the multiple-ascending-dose (MAD) study, itraconazole doses of 100, 200, and 300 mg as NCF were studied, as was one dose level (200 mg) as an HBPCD solution. Samples were collected in heparinized tubes at various time points and were analyzed by high-performance liquid chromatography to allow full pharmacokinetic analysis both after the first dose and on day 7. The results of both the SAD and the MAD studies indicated that there was a dose dependency in the half-life of itraconazole from the novel formulation, increasing from 44 h (100 mg) to more than 150 h (300 mg) once steady state was achieved. Similar dose-dependent effects were observed for the hydroxy metabolite. The areas under the concentration-time curves for itraconazole and hydroxyitraconazole were also dose dependent. The pharmacokinetic profiles after 200-mg doses of itraconazole as NCF and HPBCD formulations were comparable with respect to the terminal half-life, both after a single dose and at steady state. NCF may provide an alternative to the HPBCD solution for the further optimization of antifungal treatment with itraconazole.