造血干细胞移植患儿伏立康唑治疗药物浓度监测及影响因素分析

Therapeutic Drug Monitoring and Influencing Factors of Voriconazole Serum Concentration in Pediatric Hematopoietic Stem Cell Transplantation Patients

目的探讨CYP2C19基因多态性和非遗传因素对造血干细胞移植患儿伏立康唑血药浓度的影响并分析治疗药物浓度监测结果,为个体化给药提供参考。方法纳入60例造血干细胞移植患儿伏立康唑稳态谷浓度492例,利用荧光原位杂交技术检测患儿CYP2C19*2、CYP2C19*3、CYP2C19*17基因型。采用非参数检验、多重线性回归分析相关遗传因素与非遗传因素对伏立康唑浓度的影响。结果492例谷浓度中62.8%达到治疗窗范围。在小于6岁、6~12岁、大于12岁3组年龄段患儿中日剂量/体质量、达到伏立康唑治疗窗时所需日剂量/体质量、谷浓度水平、谷浓度不同水平分布频率的差异具有统计学意义(P<0.05)。伏立康唑日剂量、CYP2C19正常代谢型、慢代谢型、是否使用质子泵抑制剂可解释13.7%的伏立康唑浓度个体差异。结论CYP2C19基因多态性、伏立康唑日剂量及是否使用质子泵抑制剂显著影响伏立康唑浓度,可结合治疗药物浓度监测指导个体化给药。

OBJECTIVE To explore the correlation between CYP2 C19 gene polymorphism,non-genetic factors and voriconazole concentration in pediatric hematopoietic stem cell transplantation patients,analyze the results of therapeutic drug monitoring for providing individual administration reference.METHODS A number of 60 pediatrics with 492 voriconazole trough concentrations were included in the study.CYP2 C19*2、CYP2 C19*3、CYP2 C19*17 genotypes were detected by fluorescence in situ hybridization.The correlation between genetic factors,non-genetic factors and voriconazole concentration were analyzed by using chi-square test,non-parametric test and multiple linear regression analysis.RESULTS 62.8%of the 492 voriconazole trough concentrations were reached the therapeutic window.The daily dose/weight,daily dose/weight for reaching therapeutic window,level of voriconazole trough concentration and distribution frequency of voriconazole concentration level were significant difference between children age less than 6,6 to 12,and more than 12 years old(P<0.05).Affecting factors such as daily dose,CYP2 C19 extensive metabolizer,poor metabolizer and coadministration with proton pump inhibitors explained 13.7%of the variability in voriconazole exposure.CONCLUSION Voriconazole concentration is affected by CYP2 C19 gene polymorphisms,daily dose,coadministration with proton pump inhibitors,which shoud be considered with therapeutic drug monitoring for individual administration.