Clinical importance of the CYP2C19*17 variant allele for voriconazole

We read with interest the article by Li-Wan-Po and colleagues on the functional and clinical implications of the recently discovered CYP2C19*17 variant allele [1]. The authors examine the available literature on the influence of the CYP2C19*17 allele on the disposition of a number of clinically used medicines including voriconazole that are metabolized by this enzyme. The authors conclude that while the CYP2C19*17 allele is associated with increased enzymatic activity, the magnitude of these changes is unlikely to be clinically significant with the possible exception of clopidogrel and tamoxifen [1]. While few studies have assessed the impact of CYP2C19*17 on voriconazole, the available evidence suggests its clinical relevance should not yet be discounted.

Voriconazole is indicated as a first line agent in the treatment of invasive pulmonary aspergillosis [2] and is known to be predominantly metabolized by CYP2C19, and to a lesser extent by CYP2C9 and CYP3A4 [3]. Voriconazole displays non-linear pharmacokinetics and high inter-individual variability [4], with CYP2C19 genotype accounting for 49% of the variance observed in apparent oral clearance [5]. Several studies have demonstrated a relationship between voriconazole serum concentrations and clinical efficacy and toxicity [6–8]. Pascual and colleagues prospectively identified that a lack of response to therapy was more common when trough voriconazole concentrations were below 1 mg l⁻¹ (46% treatment failure) than when concentrations exceeded this value (12% treatment failure) [7]. Neurological toxicity due to voriconazole has been associated with concentrations above 5.5 mg l⁻¹[9], highlighting the narrow therapeutic range associated with this antifungal [10].

Wang et al. [11] examined the pharmacokinetics of voriconazole following a single oral dose in CYP2C19*17 heterozygotes (CYP2C19*1/*17) compared with homozygous extensive metabolizers (CYP2C19*1/*1) and poor metabolizers (CYP2C19*2/*2) [11], as discussed in the review by Li-Wan-Po et al.[1]. While the sample size was small, CYP2C19*17 heterozygotes were found to have a significantly lower systemic exposure compared with homozygous extensive metabolizers (mean AUC_0–24 3.39 and 6.18 µg h ml⁻¹, respectively) [11]. The 95% confidence intervals for the AUC_0–24 of voriconazole in people with these two genotypes do not overlap (Figure 1). Significant differences were also found between people carrying different genotypes in voriconazole half-life and clearance [11]. A later pharmacokinetic study by Weiss et al. also found that subjects carrying the CYP2C19*17 allele had a lower peak and total voriconazole exposure compared with homozygous extensive metabolizers (CYP2C19*1/*1) [5], although the magnitude of the differences were smaller than those found by Wang et al. [11].

Figure 1.

Mean AUC_0–24 and 95% confidence intervals for CYP2C19*1/*17 heterozygotes (n = 4) and CYP2C19*1/*1 homozygotes (n = 8) from Wang et al. [11]

Taken together, these studies demonstrate voriconazole exposure is reduced in subjects carrying a single CYP2C19*17 allele, potentially by up to half compared with homozygous extensive metabolizers [11]. These findings suggest subjects carrying a CYP2C19*17 allele may be at greater risk of sub-therapeutic voriconazole concentrations, and subsequently of treatment failure. The routine use of therapeutic drug monitoring for voriconazole [9] would identify low concentrations and allow dose adjustment in such patients. However, the association of low initial trough voriconazole concentrations with increased mortality [8] implies this may not ensure a positive clinical outcome in all cases.

The authors are not aware of any published studies that have investigated voriconazole metabolism in CYP2C19*17 homozygotes (CYP2C19*17/*17). It may be expected that these subjects would display further reduced voriconazole exposure when compared with homozygous extensive metabolizers, as is the case for omeprazole [1]. Furthermore, no studies have yet assessed the impact of the CYP2C19*17 allele on the pharmacokinetics of voriconazole at steady state. Considering the clinical consequences of low voriconazole concentrations, we recommend awaiting the results of larger, multiple dose studies including CYP2C19*17 homozygotes before discounting the clinical importance of the CYP2C19*17 allele for voriconazole therapy.

Competing interests

There are no competing interests to declare.