Impact ofCYP2C19,CYP3A4,ABCB1, andFMO3genotypes on plasma voriconazole in Thai patients with invasive fungal infections

AbstractVoriconazole is the first‐line antifungal choice in the treatment of invasive fungal infections (IFIs). Single nucleotide polymorphisms (SNPs) in drug‐metabolizing and transporter genes may affect voriconazole pharmacokinetics. This study aimed to determine the frequency of theCYP2C19rs4244285, rs4986893, rs72552267, and rs12248560,CYP3A4rs4646437,ABCB1rs1045642, andFMO3rs2266782 alleles and determine the association between these genetic variants and voriconazole concentrations in Thai patients with invasive fungal infections. The study comprised 177 Thai patients with IFIs in whom seven SNPs inCYP2C19,CYP3A4,ABCB1,andFMO3were genotyped usingTaqMan real‐time polymerase chain reaction (RT‐PCR) 5´ nuclease assays, and voriconazole plasma concentrations were measured by high‐performance liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). Of the 177 patients included, 31 were <12 years and 146 were ≥12 years. TheCYP2C19allele frequencies were 0.29 for*2, 0.060 for*3, 0.003 for*6, and 0.008 for*17. The allele frequency ofCYP3A4(rs4646437) was 0.26,ABCB1(rs1045642) was 0.36, andFMO3(rs2266782) was 0.16. The median voriconazole dose/weight was significantly lower in patients aged ≥12 years when compared to the patients aged <12 years (P < .001). Patients aged <12 years withCYP2C19*1/*2exhibited significantly higher median voriconazole plasma concentrations than those with theCYP2C19*1/*1(P = .038). However, there were no significant differences in median voriconazole plasma concentrations among theCYP2C19genotypes in the patients aged ≥12 years. There was a lack of association observed among theCYP3A4, ABCB1, andFMO3 genotypes on the plasma voriconazole concentrations in both groups of patients. Our findings indicate that voriconazole plasma concentrations are affected by theCYP2C19*2allele in patients aged <12 years but not in patients aged ≥12 years.