A new perspective on variation of voriconazole steady-state valley
concentration in Chinese population: CYP2C19 DNA methylation
Abstract
Background: Voriconazoleis(VRC) often used in complex therapeutic
environments for the treatment and prevention of invasive fungal
infections. The steady-state valley concentration (Cminss) of VRC not
only varies between individuals, but also within individuals, which is
difficult to fully explain by pharmacogenomic theory. It is necessary to
propose a new perspective to explain the variation of voriconazole
steady-state valley concentration. Objectives: Based on the regulation
of ADME gene expression by DNA methylation, this study aimed to explore
the effect of CYP2C19 DNA methylation level on the VRC Cminss. Methods:
In this study, 116 concentration points were divided into low
concentration group (Cminss<1.0mg/L), standard concentration
group (Cminss =1.0-5.5mg/L) and high concentration group
(Cminss>5.5mg/L) according to Voriconazole Cmin standard
range of 1.0-5.5 mg/L. The effect of CYP2C19 DNA methylation was
highlighted by predisposition score matching to exclude other
confounding factors. Results: The CYP2C19 CpG25 methylation level was
different between low concentration group and standard concentration
group (p=0.047). There was no difference in the CYP2C19 DNA methylation
between the high concentration group and the standard concentration
group, but there were significant differences in CRP
(p<0.001), Alb (p=0.007) and T-BIL (p=0.024) between the high
concentration group and the standard concentration group. Conclusions:
The VRC Cminss in the low concentration group may be related to the
methylation degree of CYP2C19 CpG25 site, while the VRC Cminss in the
high concentration group may be unrelated to the methylation degree of
CYP2C19 but related to the levels of CRP, Alb and T-BIL.