Pharmacogenetics of Voriconazole: CYP2C19 but Also CYP3A4 Need to Be Genotyped

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To the Editor: We read with great interest the article entitled “Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C19” by Moriyama et al. recently published in Clinical Pharmacology & Therapeutics.1 This article summarizes all data linking voriconazole trough concentrations and genetic variants of CYP2C19, but also proposes dosing recommendations for voriconazole treatment based on the CYP2C19 genotype.
In addition to the CYP2C19 genotype, the authors raised the possible influence of genetic variations affecting other cytochromes implicated in the voriconazole metabolism, namely, CYP3A4, 3A5, and 2C9 (paragraph entitled “Other considerations,” section Therapeutic Recommendation). In this paragraph, the authors mentioned that “genetic variation in CYP3A4, CYP3A5, and CYP2C9 appears not to significantly affect the pharmacokinetics of voriconazole” and referred to two studies that, in fact, had exactly shown the opposite.2,3 Indeed, we demonstrated in a retrospective study that the CYP3A4*22 polymorphism (rs35599367) significantly influenced voriconazole trough concentrations adjusted on the dose in 29 allograft hematopoietic stem cell transplant patients (see Figure 1a and 1b reproduced from our previously published article in Antimicrobial Agents Chemotherapy 2015).2 In addition, a retrospective Chinese study conducted in 158 patients identified another single nucleotide polymorphism (SNP) located in an intronic area of the CYP3A4 (rs4646437) as associated with higher VRC levels.3 In each of these works, the CYP2C19 genotype was also determined and the impact of genetic variants of CYP3A4 on voriconazole trough concentration was independent of the latter.2,3 Very recently, the impact of rs4646437 SNP was also confirmed in a retrospective study conducted in 86 patients by another Chinese team.4 Although these data are preliminary and need to be confirmed in independent and larger cohorts of patients treated by voriconazole and genotyped for CYP2C19, CYP34A, 3A5, and 2C9, they strongly suggest that genetic variants of CYP3A4 may significantly impact VRC trough plasma concentrations.
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