Indications
Voriconazole is indicated for the treatment of several serious fungal infections. Specifically, it is approved for use against esophageal candidiasis, candidemia, and invasive pulmonary aspergillosis. Additionally, voriconazole is effective in treating serious infections caused by Scedosporium apiospermum and Fusarium species.
Pharmacodynamics
Voriconazole functions as a fungistatic triazole antifungal agent. Its mechanism of action involves inhibiting fungal growth, which is essential in managing complex fungal infections. However, it is important to note that some patients may experience adverse reactions, such as hepatotoxicity and photosensitivity, during treatment with voriconazole.
Absorption
The absorption profile of voriconazole indicates a high oral bioavailability of approximately 96% in healthy adults. In pediatric populations, the bioavailability is reduced, averaging around 61.8%, likely due to differences in first-pass metabolism or dietary factors. Transplant patients also exhibit reduced bioavailability initially, which tends to improve over time post-transplantation. The time to maximum concentration (Tmax) following oral administration is between 1 to 2 hours. It should be noted that the presence of a high-fat meal significantly reduces the maximum concentration (Cmax) by 34% and the area under the curve (AUC) by 24%. However, pH levels do not affect voriconazole absorption. Gender differences have been observed, with females showing an increase in Cmax by 83% and AUC by 113%, although these variations do not significantly impact the medication's safety profile.
Metabolism
Voriconazole undergoes extensive hepatic metabolism, primarily through the cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP3A4. The N-oxidation process, predominantly mediated by CYP2C19, results in the formation of voriconazole N-oxide, which constitutes 72% of the circulating metabolites. CYP3A4 also contributes to N-oxidation and 4-hydroxylation. Minor roles are played by CYP3A5 and CYP3A7 in the metabolism of voriconazole. The resultant N-oxide and 4-hydroxylated metabolites are further subjected to glucuronidation and are primarily excreted in the urine.
Mechanism of Action
Voriconazole is employed in the treatment of fungal infections caused by organisms such as Aspergillus spp. and Candida spp. As a triazole antifungal, voriconazole primarily exerts fungistatic effects against various fungal pathogens. It functions by binding to 14-alpha sterol demethylase, also called CYP51, thereby inhibiting the demethylation of lanosterol within the ergosterol synthesis pathway in yeast and other fungi. The resulting deficiency in ergosterol compromises the integrity of the fungal cell membrane, impeding fungal cell growth. This growth inhibition enables the host's immune system to effectively eliminate the invading fungal organisms.
