In Vitro Activity

The mechanism of action of voriconazole, similar to that of all azole agents, is inhibition of cytochrome P450 (CYP 450)–dependent 14α-lanosterol demethylation, which is a vital step in cell membrane ergosterol synthesis by fungi [1]. For yeasts, voriconazole appears to be fungistatic, as are other azoles. However, for some filamentous organisms, voriconazole and other second-generation azoles are fungicidal [2]. This effect may relate to the stronger avidity of the new azoles for the lanosterol 14α-demethylase found in molds, compared with that found in yeasts, which may allow more-complete interruption of ergosterol synthesis and lead to cell death.

Voriconazole is active against all Candida species, including Candida krusei, strains of Candida glabrata that are inherently fluconazole-resistant, and strains of Candida albicans that have acquired resistance to fluconazole (table 1) [2–6]. In general, the MICs of voriconazole for C. albicans are 1–2 log lower than the MICs of fluconazole. For some, but not all, fluconazole-resistant strains of C. albicans, MICs of voriconazole are higher than those noted for fluconazole-susceptible strains [6]. The MICs for C. glabrata and C. krusei are higher than those for other species, but they are still in the presumed susceptible range. Voriconazole shows good in vitro activity against other yeasts, including Cryptococcus neoformans, Trichosporon beigelii, and Saccharomyces cerevisiae [7–9].

Pharmacology

Voriconazole is available in both intravenous and oral formulations. The intravenous formulation is solubilized in sulfobutyl ether β-cyclodextrin sodium (SBECD) and is infused over 1–2 h. In adults, steady-state plasma levels after intravenous infusion of 3–6 mg/kg twice daily range from 3 to 6 µg/mL [19]. Steady-state concentrations are achieved only after 5–6 days, but, if a loading dose is given, steady-state concentrations are achieved within 1 day [20]. The recommended regimen is a loading dose of 6 mg/kg every 12 h for 2 doses, followed by a maintenance dose of 4 mg/kg every 12 h.

The oral formulation of voriconazole is available as 50-mg and 200-mg tablets. When administered either 1 h before or 1 h after a meal, the bioavailability of the oral formulation is >90%. Gastric acid is not needed for absorption; fatty foods decrease bioavailability to ∼80%. In adults, after oral administration of 200 mg twice daily, steady-state plasma concentrations generally range from 2 to 3 µg/mL [21]. Patients who weigh 40 kg should receive 200 mg every 12 h, and those who weigh 40 kg should receive 100 mg every 12 h. Steady-state concentrations are achieved within 24 h if a loading dose twice the amount of the daily dosage is given on day 1

In adults, voriconazole exhibits nonlinear pharmacokinetics, which is thought to be related to saturation of metabolism [20]. There is substantial intersubject variability in the serum concentrations achieved. In children, elimination is linear, and higher dosages are required to attain the serum concentrations noted in adults [22]. Voriconazole is 58% protein bound and has a large volume of distribution. In animals and humans, concentrations in the CSF are ∼50% of plasma concentrations; concentrations in brain tissue are higher than those in the CSF. Less than 5% of the drug is excreted unchanged in the urine.

Metabolism of voriconazole occurs in the liver via the CYP450 enzyme family, including the CYP2C9, CYP3A4, and CYP2C19 isoenzymes. The metabolites do not have antifungal activity. The activity of the CYP2C19 pathway, which is the major metabolic pathway for voriconazole, is highly dependent on genetic characteristics; as many as 20% of non-Indian Asians have low CYP2C19 activity and can achieve voriconazole levels as much as 4 times higher than those noted in homozygous subjects who metabolize the drug more extensively. This “poor metabolizer ”trait is uncommon in white and black populations worldwide. There are no dosage adjustments recommended with regard to this observation at this point in time.

However, the observation that hepatic toxicity might be dose related should prompt careful attention to the monitoring of liver enzyme levels in this population. As might be predicted, drug-drug interactions (see the next section, below) are of major importance in the safe use of voriconazole.

Dosage adjustments are necessary for patients with liver dysfunction. The standard loading dose should be used but the maintenance dosage should be halved in patients with mild-to-moderate liver disease. No studies have evaluated the safety of voriconazole in patients with severe liver disease. No adjustment in the dosage of the oral formulation of voriconazole is necessary in patients with renal insufficiency. However, moderate renal insufficiency (creatinine clearance of 30–50 mL/min) results in accumulation of the intravenous vehicle SBECD, and, therefore, intravenous administration should be avoided for patients who have a creatinine clearance 50 mL/min.