Voriconazole (VRCZ) is a new triazole antifungal agent that was approved in Japan in April 2005. VRCZ is characterized by a high bioavailability and a broad spectrum of antifungal activity that includes a number of species that are refractory to other currently available antifungals, such as Candida glabrata and Candida krusei as well as Aspergillus, Fusarium, and Scedosporium species. VRCZ is available in both intravenous and oral formulations, facilitating a smooth switch from drip infusion to oral therapy. It shows excellent penetration into tissues that are sites of deep-seated mycoses, such as the lung, liver, kidney, brain and eyes. Although serum VRCZ concentrations may vary greatly, no correlation has been found between serum concentrations and efficacy or safety. For the treatment of deep-seated mycoses in patients with hematopoietic stem cell transplantation (HSCT), which is currently treated in Japan using fluconazole or amphotericin B, VRCZ is anticipated to be particularly effective for empiric and targeted therapy. A phase III clinical trial in Japan of VRCZ for the treatment of deep-seated mycoses showed that VRCZ was well tolerated and was extremely effective against aspergilloses, candidiasis, and cryptococcosis as well as against invasive pulmonary aspergillosis. An international trial of VRCZ and amphotericin B for the treatment of invasive aspergilloses that developed in immunocompromised patients after HSCT showed that VRCZ was significantly more effective. VRCZ promises to improve the treatment of deep-seated mycoses in Japan and is expected to exhibit excellent clinical effects in the future treatment of this condition.

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Voriconazole (VRCZ) is an azole antifungal agent that was developed to provide high antifungal activity against fluconazole (FLCZ)-resistant Candida, like non-albicans Canclida, as well as Aspergillus and Cryptococcus. Its pharmacokinetic properties are superior to those of FLCZ, including a high penetration into the central nervous system. It is also available as either an intravenous injection or an oral formulation, enabling the smooth transfer of patients from hospital to outpatient or home treatment and maximizing clinical efficacy and safety. VRCZ has been available for a wide variety of clinical purposes in Europe and the United States and was approved in Japan in April 2005.

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Voriconazole (VRCZ), a new-generation azole antifungal agent with a wide antifungal spectrum, like all azole agents, selectively inhibits fungal ergosterol biosynthesis. We review experimental data obtained by Pfizer's re-search group and ours on the in vitro and in vivo antifungal activity of VRCZ compared to itraconazole (ITCZ) and fluconazole (FLCZ), along with data published elsewhere. VRCZ has substantial in vitro activity against Candida spp., including FLCZ-insusceptible C. glabrata and C. krusei, Cryptococcus neoformans and other yeasts that is similar to ITCZ and superior to FLCZ. VRCZ had potent and fungicidal in vitro activity against most Aspergillus spp. and several other mycelial fungi. In vivo VRCZ activity was evaluated in guinea pig models of systemic and invasive pulmonary aspergillosis and of systemic candidiasis due to a FLCZ-resistant C. albicans and C. krusei, using ITCZ and FLCZ as reference drugs. In all of these animal models, VRCZ was more effective than similar or higher doses of reference drugs in the survival of infected animals, clearance of challenged pathogenic fungi, and/or reduction of fungal burden in infected tissues. VRCZ thus appears to be an attractive option in the treatment of invasive and disseminated fungal infections.

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Vohconazole (VRCZ), a broad-spectrum triazole, is served in two dosage forms-injection and tablet. VRCZ shows excellent absorption and high bioavailability even in oral administration. It must be administered, how-ever, between meals because absorption is delayed after fatty food intake compared to fasting administration.
VRCZ shows excellent tissue penetration with the concentration in tissues exceeding the MIC of major fungal species. VRCZ also penetrates well into the cerebrospinal fluid (CSF). In humans, 1-10 h after receipt of VRCZ, the ratio of CSF to plasma concentration ranged from 0.22 to 1.0 (median, 0.46).
Three microsome enzymes are involved in VRCZ metabolism, CYP2C9, CYP2C19, and CYP3A4, and polymorphisms in CYP2C19 may result in individual differences in VRCZ metabolism. In a phase I study, subjects classified as poor metabolizers (PM), which would include 19% of the Japanese population, had higher serum VRCZ concentrations than other subjects. Because VRCZ concentration varies greatly among individuals of the same genotype and the condition of a patient, however, a concomitant drug or the like will influence the exposure of VRCZ, it is difficult to adjust the amount of VRCZ by genotyping alone.
In patients with renal damage, VRCZ dose adjustment is not required when administered in tablet form because VRCZ is not excreted by the kidneys. One agent added to the injection formula, sulfobutylether-β-cyclodextrin, is excreted by the kidneys, however, and may accumulate in patients with renal damage. Children show lower serum VRCZ concentration than adults, probably due to higher enzyme activity and more rapid drug clearance.
This drug is given with a loading dose. The loading dose in intravenous administration is 6 mg/kg administered twice a day every 12 hours. For dosage from day 2 onward, it is recommended to administer 3 mg/kg for maintenance therapy and 4 mg/kg twice a day if the effect is insufficient with that amount. With oral administration, it is appropriate to administer 300 mg twice a day every 12 hours for the loading dose and 150-200 mg for the maintenance dose from the second day 2 onward.

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Aspergillus has recently replaced Candida as the primary cause of death due to fungal infection, making it urgent to find drugs with good activity against Aspergillus. The new azole antifungal voriconazole (VRCZ) showed greater effectiveness and tolerability against aspergillosis than the conventional gold standard, Amphotericin B (AMPH). It also improved the survival of invasive aspergillosis patients with unfavorable prognosis. Earlier treatment with VRCZ would be expected to result in even better effectiveness and survival. Empiric treatment with VRCZ is expected to effectively prevent the onset of aspergillosis in high-risk patients.

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This was an uncontrolled multicenter study to assess the clinical usefulness (efficacy and safety) of voxiconazole (VRCZ) for deep-seated mycosis.
Efficacy was assessed in 65 of 100 subjects given the study drug, while safety was assessed in 100 subjects.
For oral therapy, 300 mg of VRCZ was administered twice as the loading dose on Day 1, and patients then received 150-200mg twice daily on subsequent treatment days. For intravenous therapy, 6 mg/kg of VRCZ was administered twice as the loading dose on Day 1, and the maintenance dose for subsequent treatment days was 3mg/kg twice daily or in the case of severe mycosis, 4 mg/kg twice a day. When plasma VRCZ concentrations were equal to or greater than 2.5 μg/mL on Day 3 of oral and intravenous administration, dosages were decreased on Days 5-7. A switch from intravenous to oral formulation (switch therapy) was allowed after intravenous therapy had been given for at least 3 days. Treatment lasted 12 weeks. Global efficacy was 68.3%(28/41) for aspergillosis, 91.7%(11/12) for candidiasis, and 100%(8/8) for cryptococcosis.
Global efficacy for primary therapy was 91.2%(31/34) and that for salvage therapy 61.3%(19/31).
Eradication in the 65 cases evaluated for efficacy was 69.2%(9/13) for Aspergillus spp. and 91.7%(11/12) for Candida spp.
Treatment-related adverse events were reported in 78 of 100 cases. The most common adverse events were photophobia (25.0%), visual disturbance (24.0%), vomiting (8.0%), hepatic function abnormalities (8.0%), headache (8.0%), and increased γ-GTP (7.0%). Vision-related adverse events were transient and reversible in all cases. Most treatment-related adverse events were mild to moderate in severity.
No relationship was seen between plasma VRCZ concentrations and either the efficacy or safety of this drug.
These results indicate that VRCZ is useful for the treatment of severe or intractable deep-seated mycosis.

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In Japan, fungal infections, predominantly by Aspergillus and Candida, are a major cause of mortality in patients with acute myelogenic leukemia and after hematopoietic stem cell transplantation. A questionnaire revealed that antifungal therapy in leukemia, patients, Amphotericin B (AMPH-B) or fluconazole (FLCZ) was chiefly used for prophylaxis and that FLCZ was predominantly used for empiric treatment. AMPH-B was chiefly used for targeted therapy against aspergillosis, but was often achninistered in insufficient doses, probably because of concern about side effects. Voriconazole is a new azole antifungal agent that has a structure similar to that of FLCZ and has strong activity against a wide range of fungi with low or no susceptibility to FLCZ, including Candida, Aspergillus, and Cryptococcus. It is promising for targeted therapy, and may also be appropriate for empiric treatment of candidiasis or aspergillosis.

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