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.
Highlights
With the increasing incidence of malignant tumors, acquired immune deficiency syndrome, and organ transplantation, the morbidity and mortality of invasive fungal infections are rising and have gradually become one of the major threats to human health in recent years (Sanguinetti et al, 2019)
It is found that intra- and inter-individual variabilities of VRC plasma trough concentrations (Cmin) depend on age, actual body weight, cytochrome P450 (CYP450) polymorphisms including CYP2C19, CYP3A4, and CYP3A5, liver functions, hypoproteinemia, inflammation, and drug–drug interactions (DDIs) (Chawla et al, 2015; GautierVeyret et al, 2015)
Our results suggested that allelic mutations of CYP2C19, CYP3A4, and CYP3A5 can affect VRC Cmin/dose, but different single-nucleotide polymorphisms (SNPs) of CYP450 have different effects
Summary
With the increasing incidence of malignant tumors, acquired immune deficiency syndrome, and organ transplantation, the morbidity and mortality of invasive fungal infections are rising and have gradually become one of the major threats to human health in recent years (Sanguinetti et al, 2019). VRC is widely used to prevent and treat invasive fungal diseases and recommended by guidelines as the first-line therapy (Ullmann et al, 2018). It was gradually found that VRC had great individual differences. It is very important to clarify the factors affecting VRC concentrations in clinical practice. It is found that intra- and inter-individual variabilities of VRC Cmin depend on age, actual body weight, CYP450 polymorphisms including CYP2C19, CYP3A4, and CYP3A5, liver functions, hypoproteinemia, inflammation, and drug–drug interactions (DDIs) (Chawla et al, 2015; GautierVeyret et al, 2015). CYP450 polymorphisms and CYP-mediated drug interactions are important determinants of intra- and inter-individual variabilities of VRC
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