Itraconazole is an anti-fungal agent of the triazole family that has been shown to exhibit potent activity against fungi of Candida including non-albicans Candida and Aspergillus, . Currently, only capsule form is available for clinical use. However, with the development of a technique to dissolve the drug in hydroxypropyl-β-cyclodextrin, itraconazole oral solution and injection have begun to be developed. Itraconazole oral solution is better absorbed from the digestive tract capsule form. Itraconazole injection is administered at a loading dose level (200 mg/day in two divided doses) on the first two days, to allow rapid increase and maintenance of the plasma level of the drug to the level needed for the treatment of systemic fungal infections.
In foreign countries, trials of targeted therapy and empiric therapy using itraconazole oral solution and injection administration have been carried out and obtained excellent results. In regard to targeted therapy for patients with invasive aspergillosis (including many cases failure to intravenous amphotericin B (AMPH) therapy), itraconazole injection treatment followed by itraconazole capsules has obtained excellent results, with a remission (remission + partial remission) rate of 32% at the end of the injection treatment and 48% at the end of the study. In regard to empiric therapy for cases of persistent fever due to fungal infection (associated with neutropenia and failure to broad-spectrum antimicrobial agents), the efficacy of itraconazole injection and oral solution was found to be comparable to that of intravenous AMPH therapy, with, in addition, a significantly lower incidence of adverse reactions (nephrotoxicity, etc.) and dropouts.
In Japan, itraconazole capsules began to be marketed in 1993, and they have been used clinically for the treatment of skin and systemic fungal infections. When itraconazole oral solution and injection become available, the drug may become one of the major alternatives for the treatment of systemic fungal infections.

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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 100mg 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 400mg 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 100mg stabilized by day 9, and in repeated administration of 200mg, 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.

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Itraconazole (ITCZ) has broad-spectrum antifungal activity and is difficult to dissolve into water. A new formulation of ITCZ, an oral solution, was recently developed. ITCZ is combined with hydroxypropyl-β-yclodextrin (HP-β-CD), a vehicle that improves the solubility of ITCZ.
This open randomized trial evaluated the clinical usefulness of ITCZ oral solution over capsules in thetreatment of oropharyngeal candidiasis. ITCZ was administered orally at a dose of 200 mg a day for 7 days at 39 centers (41 clinical departments). If the subject was not cured after the 7 days of treatment and the total symptom score decreased from the baseline on Day 8, treatment was continued for an additional 7 days if necessary.
ITCZ oral solution showed noninferiority to ITCZ capsules in global improvement at the primary endpoint, i. e., 70.3%(52/74) for ITCZ oral solution and 49.4%(42/85) for ITCZ capsules. Global improvement at final assessments was 78.4%(58/74) for ITCZ oral solution and 682%(58/85) for ITCZ capsules. These results show that the clinical response for ITCZ oral solution is faster than that of ITCZ capsules and administering treatment for 7 days more improved the response in patients.
The mycologic eradication of ITCZ oral solution versus ITCZ capsules was 71.6%(53/74) versus 32.9%(28/85) on day 8, 69.0%(20/29) versus 43.2%(19/44) on day 15. At both assessment times, the mycological efficacy of ITCZ oral solution was significantly higher (p<0.0001, p=0.006) than that of ITCZ capsules.
Overall, most treatment-related adverse events were mild in both groups. All had symptoms disappear or relieved during treatment or follow-up. With ITCZ oral solution, mild gastrointestinal events are observed, but they are probably due to HP-β-CD.
In conclusion, ITCZ oral solution 200 mg once daily under fasting was shown to have an early effect andgood response in patients with early-stage oropharyngeal candidiasis.

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We investigated the efficacy and safety of Itraconazole (ITCZ) in patients with deep mycosis, evaluating intravenous injection of ITCZ (200 mg) for 2 weeks (twice a day for the first two days, then once a day for the remaining 12 days) prior to the oral administration of ITCZ capsules (200 mg) twice a day.
Total efficacy was 67.7%(21/31 cases). The efficacy in aspergillosis patients was 57.9%(11/19 cases), 71.4%(5/7) in candidiasis patients, and 100%(5/5) in cryptococcosis patients. No difference was seen in the incidence of adverse events in injection and capsule administration, and most observed adverse events of ITCZ were already known.
ITCZ plasma trough concentration after two days of injection (200 mg twice a day) reached a level (811.3±316.0 ng/mL, Mean ± S. D., n=42) efficient in treating conditions caused by primary underlying mycoses (Aspergillus, Candida, Cryptococcus), and high plasma was maintained continuously through administration of ITCZ capsules.
ITCZ injection reaches efficient plasma concentration rapidly compared to ITCZ capsules. ITCZ injection is effective for serious and acute conditions but the approved maximum dose of 200 mg/day for ITCZ capsules is not effective in treating deep mycosis.
Plasma concentration reached by ITCZ injection is continuously maintained through the administration of ITCZ capsules (200 mg, twice a day). We concluded that the first 2 weeks of injection prior to oral administration is effective in treating deep mycosis.

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