Pharmacokinetics of itraconazole after intravenous and oral dosing of itraconazole‐cyclodextrin formulations

The current research evaluated and compared the efficacy of hydroxybutenyl‐β‐cyclodextrin (HBenBCD) and hydroxypropyl‐β‐cyclodextrin (HPBCD) as enhancers of itraconazole solubility and oral bioavailability. At 10 wt% cyclodextrin, 17‐fold and 3.8‐fold increases in itraconazole aqueous solubility were observed in the presence of HBenBCD and HPBCD, respectively. Significant differences in the dissolution of itraconazole in the presence of these two cyclodextrins were also observed. Itraconazole pharmacokinetics is known to exhibit a significant food effect. However, testing in biorelevant media indicated that no food effects should be observed after oral administration of itraconazole:HBenBCD complexes. Formulations of itraconazole with HBenBCD were prepared and these complexes, along with the commercial forms of itraconazole with and without HPBCD (Sporanox®) were administered to male Sprague-Dawley rats by oral and intravenous routes. Intravenous administration of itraconazole formulated with HBenBCD resulted in a higher AUC relative to Sporanox®. When administered as oral solutions, the itraconazole:HBenBCD formulation provided higher oral bioavailability than the Sporanox® oral solution. When administered as solid formulations, the itraconazole:HBenBCD solid formulation provided a 2× increase in oral bioavailability relative to the Sporanox® solid formulation. No food effects were observed with the itraconazole:HBenBCD solid dosage forms. Drug/metabolite ratios were dependent upon the dosage form. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 3100-3116, 2007