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.

Aims: To assess the impact of cytochrome P450 (CYP) 2C19 polymorphisms on the clinical efficacy and safety of voriconazole. Methods: We systematically searched PubMed, EMBASE, CENTRAL, ClinicalTrials.gov, and three Chinese databases from their inception to March 18, 2021 using a predefined search algorithm to identify relevant studies. Studies that reported voriconazole-treated patients and information on CYP2C19 polymorphisms were included. The efficacy outcome was success rate. The safety outcomes included overall adverse events, hepatotoxicity and neurotoxicity. Results: A total of 20 studies were included. Intermediate metabolizers (IMs) and Poor metabolizers (PMs) were associated with increased success rates compared with normal metabolizers (NMs) (risk ratio (RR): 1.18, 95% confidence interval (CI): 1.03~1.34, I2=0%, p=0.02; RR: 1.28, 95%CI: 1.06~1.54, I2=0%, p=0.01). PMs were at increased risk of overall adverse events in comparison with NMs and IMs (RR: 2.18, 95%CI: 1.35~3.53, I2=0%, p=0.001; RR: 1.80, 95% CI: 1.23~2.64, I2=0%, p=0.003). PMs demonstrated a trend towards an increased incidence of hepatotoxicity when compared with NMs (RR: 1.60, 95%CI: 0.94~2.74, I2=27%, p=0.08), although there was no statistically significant difference. In addition, there was no significant association between CYP2C19 polymorphisms and neurotoxicity. Conclusions: IMs and PMs were at a significant higher success rate in comparison with NMs. PMs were significantly associated with an increased incidence of all adverse events compared with NMs and IMs. Researches are expected to further confirm these findings. Additionally, the relationship between hepatotoxicity and CYP2C19 polymorphisms deservers clinical attention.