Monitoring Voriconazole Pharmacogenomics and Plasma Concentrations in the Treatment and Prevention of Invasive Fungal Disease for Chinese Hematological Patients

Background Voriconazole has been widly used in treatment and prevention invasive fungal disease for immunodeficiency hematological patients. And the voriconazole plasma drug levels were associated with its efficacy and toxicity. The hepatic cytochrome P450 isoenzyme 2C19 plays a important role in voriconazole metabolism. However if CYP2C19 genetic polymorphism can result in voriconazole metabolism and drug plasma level in setting of Asian population especially in hematologic patients is unknown.

ObjectiveTo evaluate the effect of CYP2C19 polymorphism on the voriconazole (VCZ) plasma concentration of patients with hematological disease and the value of serial monitoring voriconazole plasma concentrations in the treatment and prevention of invasive fungal disease(IFD).

Methods Between January to August 2016, 76 hematological patients who received voriconazole for the treatment or prevention of invasive fungal disease were enrolled in this study. The population CYP2C19 polymorphism of voriconazole were performed using PCR-Pyrosequencing. The trough plasma concentrations of vriconazole (C_trough) was determined using high-performance liquid chromatography (HPLC).

Results1. Genotyping for CYP2C19 polymorphic isoenzyme variations showed that 32 subjects (43.42%) for the CYP2C19 wild-type, 43 (56.58%) for the CYP2C19 no-wild-type. 2. 45 of 76 patients received voriconazole intravenous administration, Based on the genotype analysis, 45 subjects were identified as extensive metabolizers' group for EMs (CYP2C19*1/*1), poor metabolizers' group for IMs+PMs (CYP2C19 * *1/*2,*1/*3,*2/*3,*2/*2,*3/*3), and there was a significant difference between C_trough values in the two groups (1.66±1.86ug/ml vs 3.30±2.35ug/ml, p=0.00). 3. The C_trough of the 45 patients were detected for 119 times totally. The medium of the C_trough 45 hematological patients were described. Lack of response to therapy was more frequent in patients with voriconazole levels <1.5mg/L (23.5%) than in those with voriconazole levels >1.5mg/L (21.4%])( p=0.87). And the risk of adverse events was more frequent in patients with voriconazole levels >5.5mg/L (40.0%) than in those with voriconazole levels <5.5mg/L (25.0%) (p=0.49). Furthermore, the C_trough values of patients with adverse events is higher than the others(3.21±2.46ug/ml vs 2.17±2.14 ug/ml, p=0.042).

Conclusions The single-center study showed that the mutation of CYP2C19 was quite common in Chinese hematological patients. Patients with CYP2C19 wild-type phenotype are extensive metabolizers, their C_trough of voriconazole are significantly lower than patients with CYP2C19 non-wild-type phenotype (poor metabolizers). Appropriate concentrations of vriconazole can improve the effiency of therapy and safety outcome.