Impact of CYP2C19 genotype on voriconazole exposure and effect of voriconazole on the activity of CYP3A in patients with haematological malignancies

Abstract

1. Voriconazole (VRC) is a first-line drug for the treatment of invasive fungal infections (IFIs) and an inhibitor of CYP3A activity. The aims of this study are to investigate the influence of related factors on the plasma concentration of voriconazole and the effect of voriconazole on the activity of CYP3A in patients with haematological malignancies.

2. A total of 89 patients received an initial dose of 6 mg/kg followed by 4 mg/kg every 12 h were included in the study. Blood samples were collected before and 2 h after administration for subsequent testing and for the extraction of DNA samples. Voriconazole and voriconazole N-oxide in the plasma were detected by LC-MS/MS. The effect of voriconazole on CYP3A activity was evaluated by the ratio of the endogenous biomarkers 6β-hydroxycortisol and cortisol.

3. During the study period, the overall incidence of adverse reactions was 33.6% (with no deaths). The metabolite type of CYP2C19 and combined use of CYP2C19 enzyme inhibitors both had a significant impact on voriconazole exposure. Voriconazole has a long-lasting and potent inhibitory effect on CYP3A activity. The exposure of CYP3A substrate in combination with metabolic enzyme inhibitors voriconazole could increase. Therefore, the combination uses with voriconazole need to be considered carefully and assessed adequately.

Keywords:

• Voriconazole
• CYP2C19
• CYP3A
• endogenous biomarker
• drug–drug interactions

Ethics approval

The experimental protocol of the study was approved by the ethics committee of Jiangsu Provincial People’s Hospital (approval number: 2015-sr-206). The studies involving human participants were reviewed and approved by the Ethical Committee of Jiangsu Province Hospital.

Consent to participate

Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

Disclosure statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Data availability statement

The datasets generated for this study are available on request to the corresponding authors.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

Outstanding Young and Middle-aged Talents Support Program of the First Affiliated Hospital with Nanjing Medical University (Jiangsu Province Hospital).