Vol.54 No.S-1 October 2006

Single- and multiple-dose pharmacokinetics of Itraconazole oral solution in healthy men

Munetetsu Tei¹⁾, Miki Yamamoto¹⁾, Koichi Inoue²⁾ and Shinichi Torii²⁾

¹⁾Bio-iatric Center, Kitasato Institute, 5-9-1 Shirokane, Minato-ku, Tokyo, Japan
²⁾Clinical Pharmacology Dept., Janssen Pharmaceutical K.K.

Abstract

Itraconazole (ITCZ) has broad-spectrum antifungal activity, and ITCZ capsules have already been used for systemic and superficial fungal infections. A new formulation of ITCZ, an oral solution, has recently been developed. ITCZ is combined with hydroxypropyl-β-cyclodextrin (HP-β-CD), a vehicle that improves the solubility of ITCZ.
The pharmacokinetics of the ITCZ oral solution were examined both in single and repeated administration in healthy men. The effect of food intake in the single administration of ITCZ oral solution 100 mg was evaluated when ITCZ oral solution was administered under fasting or under fed conditions. The Cmax of the fasting group is 1.7-fold higher than the fed group, and the area under the plasma concentration-time curve from time zero to infinity (AUC_0→∞) of the fasting group is 1.1-fold higher than the fed group. In single administration studies of ITCZ oral solution of 100, 200, 300, and 400 mg under fasting condition, Cmax and AUC_0→∞ of ITCZ and hydroxy-itraconazole (OH-ITCZ: active metabolite) increased dose-dependently and there was no difference between dosage groups both in the time to reach Cmax (Tmax) and the terminal half-life (t_1/2). In repeated administration studies, no significant drug accumulation was observed. The trough plasma concentration of ITCZ and OH-ITCZ in repeated administration of ITCZ oral solution 100 mg stabilized by day 9, and in repeated administration of 200 mg, stabilization is reached by day 12. With ITCZ oral solution, mild softened feces are observed, but they are probably due to the side effect of HP-β-CD. ITCZ oral solution is well tolerated by healthy men. From the results, it is also clear that the plasma concentration of ITCZ increased faster and Cmax is higher with ITCZ oral solution than capsules, and the absorption of ITCZ oral solution is regular.

Key word

itraconazole, oral solution, pharmacokinetics, hydroxypropyl-β-cyclodextrin

Received

June 1, 2006

Accepted

August 23, 2006

Jpn. J. Chemother. 54 (S-1): 6-17, 2006