CYP2C19 genotype variability: Effects on voriconazole and metabolite levels

Published: June 15th, 2014

Category: Stories

Teresa Vo, PharmD, 2013-2014 PGY2 Resident in Personalized Medicine

In a prospective evaluation of 95 patients treated with voriconazole (Vfend—Pfizer) over a 2-year period, CYP2C19 and CYP2C9 genotypes were not major determinants of voriconazole metabolism. However, the CYP2C19 *2/*2 genotype was associated with significantly higher mean serum voriconazole levels, and lower levels of the voriconazole N-oxide metabolite.

Main Points

Voriconazole is a broad-spectrum antifungal agent commonly used for empiric or established infection with aspergillosis in immunocompromised patients. Therapeutic drug monitoring is often employed with voriconazole due to its narrow therapeutic index and variable plasma concentrations. The contribution of CYP2C19 genotype to this variability in voriconazole levels has been debated; additional data are needed to guide appropriate clinical use of this information.

Zonios and colleagues prospectively evaluated the association between voriconazole toxicity and serum concentrations of voriconazole or its metabolites, and the role of CYP2C9 or CYP2C19 genotype. Investigators identified 95 primarily white patients enrolled at the National Institutes of Health Clinical Center (2005 to 2007) who received voriconazole. Voriconazole toxicity was assessed by structured interviews and weekly serum trough concentrations. High performance liquid chromatography was used to measure serum concentrations of voriconazole and its metabolites (4-hydroxyvoriconazole and voriconazole N-oxide)

The most commonly observed adverse effects included hallucinations (n = 16), visual changes (n = 17), photosensitivity (n = 10), and hepatotoxicity (n = 6). Mean voriconazole (but not voriconazole metabolite) concentrations were significantly higher in patients experiencing hallucinations compared to patients without hallucinations (4.53 vs. 2.52 μg/mL; P = 0.04). Neither photosensitivity nor hepatotoxicity were correlated with serum concentrations of voriconazole or its metabolites.

A total of 4 study patients were homozygous for the slow metabolizer CYP2C19 phenotype (CYP2C19*2/*2), 18 were heterozygotes (*1/*2), and 63 were *1/*1. Voriconazole levels were significantly higher (4.3 vs. 2.5 μg/mL), and N-oxide metabolite levels significantly lower (1.6 vs. 2.5 μg/mL), in CYP2C19 *2/*2 patients as compared with CYP2C19 *1/*1 patients. There were no effects of CYP2C19 *1/*2 or CYP2C9 genotypes on levels of voriconazole or its metabolites.

Clinical Implications

Study results are notable due to the need to better understand any existing relationships between genetic variability and voriconazole serum concentrations. Findings support effects of the CYP2C19 *2/*2 allele on voriconazole serum concentrations, although investigators point out that these effects were relatively small. Presence of the CYP2C19 *2/*2 allele was associated with 75% and 33% increases, respectively, in mean voriconazole and 4-hyroxy levels, and a 35% decrease in voriconazole N-oxide levels. Consistent with prior studies, CYP2C9 genotype did not correlate with changes in blood levels.

Study limitations included a small sample size, inclusion of patients receiving primarily empiric or prophylactic doses of voriconazole, and no assessment or monitoring of patient compliance with voriconazole therapy. Additionally, approximately 35% of patients received a fixed dose of voriconazole 200 mg twice daily. Investigators recognized that the “impact of low blood levels on efficacy cannot be assessed with confidence,” given the lack of therapeutic drug monitoring and the use of empiric or prophylactic doses of voriconazole within this patient population.

FDA labeling acknowledges the involvement of CYP2C19 genetic polymorphisms on voriconazole pharmacokinetics for informational purposes. Evidence for the CYP2C19-voriconazole gene-drug pair Dutch Pharmacogenetics Working Group is categorized as level B by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and level 2A by the Pharmacogenomics Knowledgebase (PharmGKB). The recommends serum concentration monitoring for voriconazole in CYP2C19 intermediate and poor-metabolizer phenotypes based on moderate-quality clinical evidence, with possible minor clinical effects resulting from genetic variability.

Reference

Zonios D et al. Voriconazole metabolism, toxicity, and the effect of cytochrome P450 2C19 genotype. J Infect Dis. 2014;209:1941–8.