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Pharmacology: Pharmacodynamics: Voriconazole is a triazole antifungal agent. The primary mode of action of Voriconazole is the inhibition of fungal cytochrome P450 (CYP-450)-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with subsequent loss of ergosterol in the fungal cell wall and may be responsible for the antifungal activity of Voriconazole. Voriconazole has a broad spectrum of activity against all Candida species, including fluconazole-resistant strains, as well as Aspergillus spp., Scedosporium spp., and Fusarium spp.
Pharmacokinetics: Absorption of Voriconazole is rapid and almost complete (oral bioavailability of 96% in adults and 45%-80% in children 2 to younger than 12 years) when given in the fasting state. Peak plasma Voriconazole concentrations are achieved 1-2 hours following a dose. In adults, steady state concentrations are achieved within 24 hours if a loading dose is administered or after 5-7 days if a loading dose is not administered. When Voriconazole are administered with high fat meals, the mean Cmax and AUC are reduced.
In pediatric patients < 12 years, the full pharmacokinetic profile for Voriconazole is not completely defined and for patients < 2 years, the data is sparse. In children 2 to younger than 12 years, current data suggest Voriconazole undergoes a high degree of variability in exposure with linear elimination at lower doses and nonlinear elimination in higher dose. Therefore, to achieve similar AUC as adults, increased dosage is necessary in children.
The volume of distribution at steady state for Voriconazole is estimated to be 4.6 L/kg. Plasma protein binding is estimated to be 58%. Voriconazole diffuses into CSF about 50% of plasma concentration.
Voriconazole is metabolized by hepatic cytochrome P450 isoenzyme, CYP2C19, CYP2C9 and CYP3A4. The major metabolite of Voriconazole is N-oxide which has minimal antifungal activity.
Voriconazole is eliminated via the hepatic metabolism, with less than 2% of the dose excreted unchanged in the urine. As a result of nonlinear pharmacokinetics, the terminal half-life of Voriconazole is dose dependent.
