voriconazole

Research Excerpts

Overview

Voriconazole is a triazole antifungal drug that inhibits ergosterol synthesis and has broad activity against yeast and molds. It is a widely used antif fungus agent in immunocompromised patients, but its utility is limited by its variable exposure and narrow therapeutic index.

Effects

Voriconazole has a high bioavailability, an high protein binding percentage in plasma and is metabolized in liver via CYP2C19. The drug has been used with success in immunocompromised patients with invasive fungal infections.

Voriconazole has the potential for retinoid-like side-effects and facial erythema. The drug has been associated with cutaneous squamous cell carcinoma in transplant patients but less is known about the risk in less severely immunosuppressed patients.

Actions

Voriconazole (VCZ) displays highly variable pharmacokinetics affecting treatment efficacy and safety. It can cause potentially serious visual side effects.

Treatment

Voriconazole treatment of human keratinocytes potentiates UV-induced apoptosis and activation of the p38 MAP kinase and 53BP1 UV stress response pathways. Mice treated with voriconzole or fluconazole administered intravaginally at >or=0.5 mg/kg exhibited a reduced fungal burden.

Toxicity

21 adult asthmatics with SAFS and ABPA were treated with 10mg of NAB (Fungizone) twice daily. Despite the short duration of exposure, worsening of renal function or newly emerged renal adverse events were reported in 53% of amphotericin B-treated patients. It is possible that the utility of voriconazole therapeutic drug monitoring to improve clinical efficacy or decrease adverse events may be  beneficial.

Pharmacokinetics

A population pharmacokinetic model of voriconazole was successfully established in Chinese hematopoietic stem cell transplantation patients. For subjects receiving 200 mg twice daily with phenytoin, the day 21/day 7 ratios for voriconsazole Cmax and AUCtau were 60.

Compound-Compound Interactions

Voriconazole (VCZ) was tested for antifungal activity against Aspergillus fumigatus hyphae alone or in combination with neutrophils or monocytes. Miltefosine demonstrated synergy in 8/20 (40%) and 4/ 20 (20%) instances when combined with posaconazole and voriconsazole.

Bioavailability

Fluconazole and voriconazole are well absorbed and exhibit high oral bioavailability. Oral bioavailability has been claimed to be almost 100%, facilitating a change from intravenous to oral application without dose adjustment.

Dosage Studied

Voriconazole pharmacokinetics is non-linear, making dosage adjustments more difficult. The suggested steady-state dosage of 200 mg twice a day has to be increased to prevent disease progression.