Effects of cytochrome P450 3A4 and non-genetic factors on initial voriconazole serum trough concentrations in hematological patients with different cytochrome P450 2C19 genotypes

Abstract

1. Polymorphisms of cytochrome P450 2C19 (CYP2C19) is an important factor contributing to variability of voriconazole pharmacokinetics. Polymorphisms of CYP3A4, CYP3A5, CYP2C9 and non-genetic factors such as age, gender, body mass index (BMI), transaminase levels, concomitant medications might also affect voriconazole initial steady serum trough concentration (VIC_min) in haematological patients, but the effects were not clear. 2. Eighteen single-nucleotide polymorphisms in CYP2C19, CYP3A4, CYP3A5, CYP2C9 were genotyped. Patients were stratified into two groups according to CYP2C19 genotype. Group 1 were patients with CYP2C19*2 or CYP2C19*3, and Group 2 were homozygous extensive metabolizers. The effects were studied in different groups. VIC_min was adjusted on daily dose (VIC_min/D) for overcoming effect of dose. 3. A total of 106 blood samples from 86 patients were included. In final optimal scaling regression models, polymorphisms of rs4646437 (CYP3A4), age, BMI was identified to be factors of VIC_min/D in Group 1 (R²=.255, p < .001). Only age was confirmed as a factor of VIC_min/D in Group 2 (R²=0.144, p = .021). 4. Besides polymorphisms of CYP2C19, in individualized medication of voriconazole in haematological patients, polymorphisms of CYP3A4, and non-genetic factors as BMI, age should also be taken into account, especially for individuals with CYP2C19*2 or CYP2C19*3.