Correlation of CYP2C19 genotype with plasma voriconazole exposure in South-western Chinese Han patients with invasive fungal infections

• Published in: Medicine (Baltimore) 2019-01, Vol.98 (3), p.e14137-e14137
• Main Authors: Miao, Qiang, Tang, Jiang-Tao, van Gelder, Teun, Li, Ya-Mei, Bai, Yang-Juan, Zou, Yuan-Gao, Wang, Lan-Lan, Shi, Yun-Ying
• Format: Article
• Language: English
• Subjects: Adult; Alleles; Antifungal Agents - administration & dosage; Antifungal Agents - blood; Asian Continental Ancestry Group - genetics; Cohort Studies; Cytochrome P-450 CYP2C19 - genetics; Drug Monitoring - methods; Female; Genotype; Humans; Invasive Fungal Infections - drug therapy; Invasive Fungal Infections - genetics; Male; Middle Aged; Observational Study; Pharmacogenomic Testing; Phenotype; Polymorphism, Genetic; Retrospective Studies; Voriconazole - administration & dosage; Voriconazole - blood
• ISSN: 0025-7974; 1536-5964
• DOI: 10.1097/MD.0000000000014137

The aim of this study was to investigate the correlation between CYP2C19 genotype and dose-adjusted voriconazole (VCZ) trough concentrations (C0/dose).We analyzed the correlation between CYP2C192(681G>A), CYP2C193(636G>A), and CYP2C1917(-806C>T) genetic polymorphisms and the dose-corrected pre-dose concentration (C0/dose) in 106 South-western Chinese Han patients.The frequencies of variant alleles of CYP2C192, 3, and 17 were 29.7%, 4.25%, and 0.92%. For 49.3% of the VCZ samples, the therapeutic window between 1.5 and 5.5 μg/ml was reached. Following the first dose VCZ measurement, in subsequent samples the proportion of VCZ C0 within the therapeutic window increased, suggesting effective therapeutic drug monitoring (TDM) (P = .001). The VCZ C0 was significantly different (P = .010) between patients with normal metabolism (NMs), intermediate metabolism (IMs), and poor metabolism (PMs). The VZC C0/dose was 12.2 (interquartile range (IQR), 8.33-18.2 μg·ml/kg·day), and 7.68 (IQR, 4.07-16.3 μg·ml/kg·day) in PMs and IMs patients, respectively, which was significantly higher than in NMs phenotype patients (4.68; IQR, 2.51-8.87 μg·ml/kg·day, P = .008 and P = .014).This study demonstrated that the VCZ C0/dose was significantly influenced by the CYP2C19 genotype in South-western Chinese Han patients. In this patient population, more over-exposure was observed in patients with a CYP2C19 genotype associated with poor or intermediate metabolism. CYP2C19 genotype-based dosing combined with TDM will support individualization of VCZ dosing, and potentially will minimize toxicity and maximize therapeutic efficacy.