| Indication |
For the treatment of esophageal candidiasis, invasive pulmonary aspergillosis, and serious fungal infections caused by Scedosporium apiospermum and Fusarium spp. |
| Pharmacodynamics |
Voriconazole is a triazole antifungal agent indicated for use in
the treatment of fungal infections including invasive aspergillosis,
esophageal candidiasis, and serious fungal infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium spp. including Fusarium solani.
Fungal plasma membranes are similar to mammalian plasma membranes,
differing in having the nonpolar sterol ergosterol, rather than
cholesterol, as the principal sterol. Membrane sterols such as
ergosterol provide structure, modulation of membrane fluidity, and
possibly control of some physiologic events. Voriconazole effects the
formation of the fungal plasma membrane by indirectly inhibiting the
biosynthesis of ergosterol. This results in plasma membrane permeability
changes and inhibition of growth. |
| Mechanism of action |
Voriconazole binds and inhibits ergosterol synthesis by inhibiting
CYP450-dependent 14-alpha sterol demethylase. The inhibition of
14-alpha sterol demethylase results in a depletion of ergosterol in
fungal cell membrane. |
| Absorption |
The oral bioavailability is estimated to be 96% (CV 13%). |
| Volume of distribution |
|
| Protein binding |
58% |
| Metabolism |
Hepatic. The major metabolite of voriconazole is the N-oxide,
which accounts for 72% of the circulating radiolabelled metabolites in
plasma. Since this metabolite has minimal antifungal activity, it does
not contribute to the overall efficacy of voriconazole. |
| Route of elimination |
Voriconazole is eliminated via hepatic metabolism with less than 2% of the dose excreted unchanged in the urine. |
| Half life |
Not Available |
| Clearance |
Not Available |
| Toxicity |
The minimum lethal oral dose in mice and rats was 300 mg/kg
(equivalent to 4 and 7 times the recommended maintenance dose (RMD),
based on body surface area). At this dose, clinical signs observed in
both mice and rats included salivation, mydriasis, titubation (loss of
balance while moving), depressed behavior, prostration, partially closed
eyes, and dyspnea. Other signs in mice were convulsions, corneal
opacification and swollen abdomen. |
