Interactive Effects of Glucocorticoids and Cytochrome P450 Polymorphisms on the Plasma Trough Concentrations of Voriconazole

Abstract

Aims: To explore the interactive influence of glucocorticoids and cytochrome P450 (CYP450) polymorphisms on voriconazole (VRC) plasma trough concentrations (Cmin) and provide a reliable basis for reasonable application of VRC.Methods: A total of 918 VRC Cmin from 231 patients was collected and quantified using high-performance liquid chromatography in this study. The genotypes of CYP2C19, CYP3A4, and CYP3A5 were detected by DNA sequencing assay. The effects of different genotypes and the coadministration of glucocorticoids on VRC Cmin were investigated. Furthermore, the interactive effects of glucocorticoids with CYP450s on VRC Cmin were also analyzed.Results: The median Cmin of oral administration was lower than that of intravenous administration (1.51 vs. 4.0 mg l−1). Coadministration of glucocorticoids (including dexamethasone, prednisone, prednisolone, and methylprednisolone) reduced the VRC Cmin/dose, respectively, among which dexamethasone make the median of the VRC Cmin/dose ratio lower. As a result, when VRC was coadministrated with glucocorticoids, the proportion of VRC Cmin/dose in the subtherapeutic window was increased. Different CYP450 genotypes have different effects on the Cmin/dose of VRC. Mutations of CYP2C19*2 and *3 increased Cmin/dose of VRC, while CYP2C19*17 and CYP3A4 rs4646437 polymorphisms decreased Cmin/dose of VRC. The mutation of CYP3A5 has no significant effect. Furthermore, CYP2C19*17 mutants could strengthen the effects of glucocorticoids and decrease VRC Cmin/dose to a larger extent.Conclusion: Our study revealed that glucocorticoids reduced the Cmin/dose levels of VRC and different SNPs of CYP450 have different effects on the Cmin/dose ratio of VRC. Glucocorticoids and CYP2C19*17 mutants had a synergistic effect on reducing VRC Cmin/dose. The present results suggested that when VRC is combined with glucocorticoids, we should pay more attention to the clinical efficacy of VRC, especially when CYP2C19*17 mutants exist.

Impact of extracorporeal membrane oxygenation on voriconazole plasma concentrations: A retrospective study

“…Theoretically, the concomitant use of inducers or inhibitors of these enzymes should impact voriconazole exposure. The drug-drug interaction between voriconazole and glucocorticoids, leading to the reduced voriconazole concentration has been suggested by a number of studies previously and has been proposed to be the result of CYP induction by glucocorticoids ( Dolton et al, 2012 ; Jia et al, 2021 ; Mafuru et al, 2021 ). Dolton et al (2012) also found that coadministration of methylprednisolone and dexamethasone reduced the voriconazole concentration to a greater extent than prednisone or prednisolone.…”

“…However, in daily practice, the concentration of voriconazole varies greatly not only between patients, but also within individual patients over time ( Mangal et al, 2018 ). Voriconazole is metabolized by enzymes that predominantly include CYP2C19, CYP3A4, and CYP2C9, and the concomitant use of inducers or inhibitors of these drug-metabolizing enzymes can affect voriconazole exposure ( Blanco-Dorado et al, 2020 ; Jia et al, 2021 ; Tian et al, 2021 ). In addition, other factors, including body weight, the nonlinear pharmacokinetic properties, the cytochrome P450 2C19 genotype, liver function and inflammation, were also reported to be responsible for the large differences in voriconazole exposure ( Shi et al, 2019 ).…”

A Visual and Comprehensive Review on COVID-19-Associated Pulmonary Aspergillosis (CAPA)

“…Voriconazole and isavuconazole have mainly been evaluated in immunocompromised patients. Voriconazole is metabolized by cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4, resulting in multiple drug-drug interactions [101]. The plasma concentrations should be closely monitored as exposure in critically ill patients is highly variable, especially in those treated with ECMO [102].…”

“…However, a delay was observed in reaching voriconazole therapeutic levels (2-6 mg/L) in CAPA patients, as Reizine et al reported that the therapeutic range was achieved at day 7, with 83.3% of patients having subtherapeutic levels (<2 mg/L) at day 5 [28]. Dexamethasone, which is now the mainstay of treatment in severe COVID-19, is implicated by inducing several CYP450 enzymes and decreasing voriconazole levels [101,103]. Another explanation is that dexamethasone reduces inflammation.…”

Application of Population Pharmacokinetic Analysis to Characterize CYP2C19 Mediated Metabolic Mechanism of Voriconazole and Support Dose Optimization

“…Theoretically, co-medication with proton pump inhibitors (PPIs) or glucocorticoids might affect the metabolic activity of CYP2C19 and further altered VCZ exposure. Jia et al revealed that glucocorticoids reduced the C min /dose levels of VCZ ( Jia et al, 2021 ). But to date, the effect of above-mentioned drugs on the disposition of VCZ remains controversial.…”