}

Voriconazole

Antifungal

Drug Overview

Voriconazole, marketed under brand names Vfend and Vorizyme, is a broad-spectrum triazole antifungal agent widely used in clinical practice.

It is approved for the treatment of serious invasive fungal infections such as invasive aspergillosis, candidemia in non-neutropenic patients, and infections caused by Scedosporium and Fusarium species. Voriconazole works by inhibiting fungal cytochrome P450 14α-sterol demethylase, an enzyme critical for ergosterol synthesis, thereby disrupting the fungal cell membrane and leading to cell death.

Relevant Genes and Their Roles

The primary gene influencing voriconazole metabolism is CYP2C19. CYP2C19 encodes a liver enzyme responsible for converting voriconazole into inactive metabolites, thereby regulating the drug’s concentration in the bloodstream.

Genetic variations in CYP2C19 can lead to different metabolizer phenotypes—ultrarapid, rapid, normal, intermediate, and poor—that affect the rate at which voriconazole is cleared. A metabolizer phenotype describes how active the enzyme is; ultrarapid metabolizers clear the drug faster, while poor metabolizers clear it more slowly.

Impact of Genetics on Drug Response

Variations in CYP2C19 activity can significantly influence voriconazole exposure: ultrarapid and rapid metabolizers may have subtherapeutic levels and risk treatment failure, whereas intermediate and poor metabolizers may experience elevated drug concentrations, increasing the likelihood of toxicity. Normal metabolizers generally achieve expected therapeutic levels with standard dosing.

Expected Clinical Effects of Genetic Variation

Ultrarapid and Rapid Metabolizers

  • Effect on drug levels: Lower than expected voriconazole concentrations.
  • Clinical consequence: Risk of treatment failure due to insufficient antifungal activity.
  • Side effects: Reduced incidence of typical adverse effects; primary concern is under-treatment rather than toxicity.

Normal Metabolizers

  • Effect on drug levels: Expected therapeutic concentrations.
  • Clinical consequence: Standard efficacy; typical clinical response.
  • Side effects: Common mild to moderate effects such as visual disturbances and gastrointestinal upset.

Intermediate Metabolizers

  • Effect on drug levels: Moderately elevated voriconazole concentrations.
  • Clinical consequence: Possible enhanced efficacy but increased risk of adverse events.
  • Side effects: Moderate risk of visual disturbances, liver enzyme elevations, and neurotoxicity.

Poor Metabolizers

  • Effect on drug levels: Significantly elevated voriconazole concentrations.
  • Clinical consequence: High risk of toxicity and adverse effects.
  • Side effects: Potentially severe hepatotoxicity, visual and auditory disturbances, and neurotoxicity.

Indeterminate / Not Available

  • Effect on drug levels: Unknown.
  • Clinical consequence: No specific guidance; standard monitoring recommended.
  • Side effects: Unpredictable; follow routine safety monitoring.

Dosing Guidelines

CYP2C19 Dosing Guideline (CPIC)

Phenotype Clinical Consequence Guideline Recommendation
Ultrarapid Metabolizer Low probability of therapeutic concentrations with standard dosing. Use an alternative agent not dependent on CYP2C19 (e.g., isavuconazole, liposomal amphotericin B, posaconazole).
Rapid Metabolizer Modest probability of therapeutic concentrations. Use an alternative agent not dependent on CYP2C19 (e.g., isavuconazole, liposomal amphotericin B, posaconazole).
Normal Metabolizer Normal metabolism and expected trough levels. Initiate standard of care dosing.
Intermediate Metabolizer Higher dose-adjusted trough concentrations compared to normal. Initiate standard of care dosing.
Likely Intermediate Metabolizer Higher dose-adjusted trough concentrations compared to normal. Initiate standard of care dosing.
Poor Metabolizer High trough concentrations; increased risk of adverse events. Use an alternative agent not dependent on CYP2C19. If voriconazole is necessary, use lower than standard dose with therapeutic drug monitoring.
Likely Poor Metabolizer High trough concentrations; increased risk of adverse events. Use an alternative agent not dependent on CYP2C19. If voriconazole is necessary, use lower than standard dose with therapeutic drug monitoring.
Indeterminate No CPIC guidance available. Initiate standard starting dose with monitoring.
Not available No CPIC guidance available. Initiate standard starting dose with monitoring.

Alternative Treatment Options

Examples of alternative antifungal agents recommended for patients with CYP2C19 ultrarapid, rapid, or poor metabolizer genotypes include isavuconazole, liposomal amphotericin B, and posaconazole. These alternatives are drawn from current CPIC guidelines and are provided for informational purposes only.

Sources and References

Disclaimer: This document is for informational purposes only and is not a substitute for medical advice. Clinical decisions should be made by a qualified healthcare professional.

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