Voriconazole

Voriconazole is an inhibitor of 14α-lanosterol demethylase with IC50 value of 53nM [1].

Voriconazole is a triazole antifungal and a second-generation synthetic derivative of fluconazole. It plays its antifungal role through inhibiting cytochrome P450 (CYP 450)–dependent 14α-lanosterol demethylation, which is a vital step in the membrane ergosterol synthesis of fungi. Voriconazole has a broad antifungal spectrum. It is active against all Candida species, many Aspergillus species and other yeasts, including Cryptococcus neoformans, Trichosporon beigelii, and Saccharomyces cerevisia. Voriconazole is available in both intravenous and oral formulations. Voriconazole undergoes extensive hepatic metabolism via the cytochrome P450 enzymes, primarily CYP2C9 and CYP3A4. In addition, voriconazole also causes some side effects, such as visual disturbances, skin rashes and elevations in hepatic enzyme levels [1, 2].

References:
[1] Sabo JA, Abdel-Rahman SM. Voriconazole: a new triazole antifungal. Ann Pharmacother. 2000 Sep;34(9):1032-43.
[2] Johnson LB, Kauffman CA. Voriconazole: a new triazole antifungal agent. Clin Infect Dis. 2003 Mar 1;36(5):630-7.

Molecular and cellular responses of the pathogenic fungus Lomentospora prolificans to the antifungal drug voriconazole.[Pubmed:28362854]

PLoS One. 2017 Mar 31;12(3):e0174885.

The filamentous fungus Lomentospora (Scedosporium) prolificans is an emerging opportunistic pathogen associated with fatal infections in patients with disturbed immune function. Unfortunately, conventional therapies are hardly of any use against this fungus due to its intrinsic resistance. Therefore, we performed an integrated study of the L. prolificans responses to the first option to treat these mycoses, namely Voriconazole, with the aim of unveiling mechanisms involved in the resistance to this compound. To do that, we used a wide range of techniques, including fluorescence and electron microscopy to study morphological alterations, ion chromatography to measure changes in cell-wall carbohydrate composition, and proteomics-based techniques to identify the proteins differentially expressed under the presence of the drug. Significantly, we showed drastic changes occurring in cell shape after Voriconazole exposure, L. prolificans hyphae being shorter and wider than under control conditions. Interestingly, we proved that the architecture and carbohydrate composition of the cell wall had been modified in the presence of the drug. Specifically, L. prolificans constructed a more complex organelle with a higher presence of glucans and mannans. In addition to this, we identified several differentially expressed proteins, including Srp1 and heat shock protein 70 (Hsp70), as the most overexpressed under Voriconazole-induced stress conditions. The mechanisms described in this study, which may be directly related to L. prolificans antifungal resistance or tolerance, could be used as targets to improve existing therapies or to develop new ones in order to successfully eliminate these mycoses.

Successful treatment of Chrysosporium keratitis with voriconazole.[Pubmed:28360537]

Int Med Case Rep J. 2017 Mar 20;10:93-95.

OBJECTIVE: To report a patient with severe Chrysosporium keratitis successfully treated by Voriconazole. METHOD: Case report. RESULTS: A 37-year-old healthy male presented with irritation, pain and reduced vision in his left eye after mud contamination. Examination demonstrated corneal stromal infiltration, endothelial plaque and hypopyon. Corneal scrapings demonstrated numerous septate hyphae, and specimen cultures were positive for Chrysosporium sp. The lesion did not respond to aggressive topical 5% natamycin, 0.15% topical amphotericin B and oral itraconazole. The patient was then treated by topical 1% Voriconazole every hour. Intracameral and intrastromal Voriconazole injections (50 mug/0.1 mL) were also undertaken. The keratitis was significantly improved after Voriconazole. CONCLUSION: To the best of the authors' knowledge, this is the first report on the use of Voriconazole for Chrysosporium keratitis. Voriconazole may be an effective alternative to conventional antifungal agents in some cases of fungal keratitis. It should be considered before shifting to therapeutic keratoplasty.

Autoinhibitory properties of the parent but not of the N-oxide metabolite contribute to infusion rate-dependent voriconazole pharmacokinetics.[Pubmed:28370390]

Br J Clin Pharmacol. 2017 Sep;83(9):1954-1965.

AIMS: The pharmacokinetics of Voriconazole show a nonlinear dose-exposure relationship caused by inhibition of its own CYP3A-dependent metabolism. Because the magnitude of autoinhibition also depends on Voriconazole concentrations, infusion rate might modulate Voriconazole exposure. The impact of four different infusion rates on Voriconazole pharmacokinetics was investigated. METHODS: Twelve healthy participants received 100 mg Voriconazole intravenous over 4 h, 400 mg over 6 h, 4 h, and 2 h in a crossover design. Oral midazolam (3 mug) was given at the end of infusion. Blood and urine samples were collected up to 48 h. Voriconazole and its N-oxide metabolite were quantified using high-performance liquid chromatography coupled to tandem mass spectrometry. Midazolam estimated metabolic clearance (eCLmet) was calculated using a limited sampling strategy. Voriconazole-N-oxide inhibition of cytochrome P450 (CYP) isoforms 2C19 and 3A4 were assessed with the P450-Glo luminescence assay. RESULTS: Area under the concentration-time curve for 400 mg intravenous Voriconazole was 16% (90% confidence interval: 12-20%) lower when administered over 6 h compared to 2 h infusion. Dose-corrected area under the concentration-time curve for 100 mg over 4 h was 34% lower compared to 400 mg over 4 h. Midazolam eCLmet was 516 ml min(-1) (420-640) following 100 mg 4 h(-1) Voriconazole, 152 ml min(-1) (139-166) for 400 mg 6 h(-1) , 192 ml min(-1) (167-220) for 400 mg 4 h(-1) , and 202 ml min(-1) (189-217) for 400 mg 2 h(-1) . Concentration giving 50% CYP inhibition of Voriconazole N-oxide was 146 +/- 23 mumol l(-1) for CYP3A4, and 40.2 +/- 4.2 mumol l(-1) for CYP2C19. CONCLUSIONS: Voriconazole pharmacokinetics is modulated by infusion rate, an autoinhibitory contribution Voriconazole metabolism by CYP3A and 2C19 and to a lesser extent its main N-oxide metabolite for CYP2C19. To avoid reduced exposure, the infusion rate should be 2 h.

In vitro activities of voriconazole (UK-109,496) and four other antifungal agents against 394 clinical isolates of Candida spp.[Pubmed:9449278]

Antimicrob Agents Chemother. 1998 Jan;42(1):161-3.

Voriconazole (formerly UK-109,496) is a new monotriazole antifungal agent which has potent activity against Candida, Cryptococcus, and Aspergillus species. We investigated the in vitro activity of Voriconazole compared to those of fluconazole, itraconazole, amphotericin B, and flucytosine (5FC) against 394 bloodstream isolates of Candida (five species) obtained from more than 30 different medical centers. MICs of all antifungal drugs were determined by the method recommended by the National Committee for Clinical Laboratory Standards using RPMI 1640 test medium. Overall, Voriconazole was quite active against all the yeast isolates (MIC at which 90% of the isolates are inhibited [MIC90], < or =0.5 microg/ml). Candida albicans was the most susceptible species (MIC90, 0.06 microg/ml) and Candida glabrata and Candida krusei were the least (MIC90, 1 microg/ml). Voriconazole was more active than amphotericin B and 5FC against all species except C. glabrata and was also more active than itraconazole and fluconazole. For isolates of Candida spp. with decreased susceptibility to fluconazole and itraconazole MICs of Voriconazole were also higher. Based on these results, Voriconazole has promising antifungal activity and further in vitro and in vivo investigations are warranted.