Commentary
Voriconazole is a synthetic second generation, broad-spectrum triazole derivative of fluconazole. It exerts antifungal activities by inhibiting the cytochrome P450 (CYP)-dependent enzyme 14-α-sterol demethylase, and subsequently disrupting the cell membrane and halting fungal growth. Its FDA indications include 1) invasive aspergillosis caused by Aspergillus fumigatus or species of Aspergillus other than A. fumigatus; 2) candidemia in nonneutropenic patients and disseminated candidiasis in skin and infections in abdomen, kidney, bladder wall, and wounds; 3) esophageal candidiasis; and 4) serious fungal infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium spp., including Fusarium solani, in patients intolerant of, or refractory to, other therapy.
Voriconazole is fungicidal against Aspergillus species, and also shows excellent activity against A. terreus. Voriconazole demonstrated superior to amphotericin B deoxycholate as the first-line treatment of invasive aspergillosis in a nonblind and noninferiority trial. Voriconazole exhibits fungistatic but excellent activity against most Candida spp. which is mostly better than anti-Candida activity of fluconazole. In addition, voriconazole also has good activity against C. glabrata, C. krusei, and C. guilliermondii. Voriconazole has good to excellent in vitro activity against Fusarium spp. and Scedosporim spp. However, it has little or no activity against zygomycetes.
Voriconazole exhibits nonlinear pharmacolinetics, and undergoes metabolism by hepatic CYP2C19 (major), CYP3A4 and CYP2C9 isonezymes. Accordingly, liver disease, age, genetic polymorphism of CYP2C19, and concurrent medications may greatly affect voriconazole metabolism. Voriconazole has demonstrated approximately 100-fold variability in drug levels for individuals receiving the same dosage. Recent clinical observations have suggested that such variability may be associated with decreased efficacy or toxicity, raising the importance of voriconazole therapeutic drug monitoring.
Voriconazole is available in both parenteral and oral formulations. Systemic absorption of oral voriconazole is rapid and complete (bioavailability achieving 96%), but is reduced in the fed state. Because its intravenous vehicle (sulfobutylether-cyclodextrin, SBECD) accumulates in patients with moderate renal impairment, those with a creatinine clearance of < 50mL/min should receive only oral voriconazole. Voriconazole is generally well tolerated, and the most common adverse events were visual disturbance (20.6%, such as blurriness, color changes, and enhanced vision) and elevated transaminase levels (13%).
Clinical Studies
In this 9-year retrospective study, patients with invasive aspergillosis receiving voriconazole had better survivals than those receiving polyenes, although advances in medicine might have certain contributions. Several predictors of increased overall mortality were identified for designing better treatment strategies.
A study supported prior clinical observations that levels of voriconazole were related to its efficacy and safety. The study also demonstrated clinical improvement by level adjustments.
Universal voriconazole prophylaxis significantly decreased the rate of invasive aspergillosis from 23.5% in lung transplant recipients receiving targeted prophylaxis to 1.5%. Of note, voriconazole was discontinued due to side effects in 14% of the cases.
Combination therapy with voriconazole and caspofungin as primary therapy significantly improved survival of invasive aspergillosis in solid organ transplant recipients with renal failure and disease caused by A. fumigatus.
Review Articles
In the article, publications of drug-drug interactions of azole with other agents were comprehensively reviewed, and managements for specific interactions were suggested.
The article reviewed available publications that supported therapeutic monitoring voriconazole concentrations. Despite unstandardized therapeutic range for voriconazole, trough concentrations of approximately 1-6 µg/mL were recommended in most studies.
Voriconazole is recommended as the first-line choice for aspergillosis in this updated and comprehensive guideline.
Adverse Drug Reactions and Warnings
FDA Information
Manufacturer/Distributor Product Information