新疆维吾尔族异基因造血干细胞移植高危患儿的伏立康唑血浆谷浓度的分布特征及对疗效和不良反应的影响

Distribution characteristics of voriconazole plasma trough concentration in Xinjiang Uygur children at high risk of allogeneic hematopoietic stem cell transplantation and its effect on efficacy and adverse reactions of voriconazole

目的:评估伏立康唑血浆谷浓度测定在治疗和预防新疆维吾尔族异基因造血干细胞移植(hematopoietic stem cell, HSCT)高危患儿真菌感染的分布特征,并探讨影响伏立康唑血浆谷浓度的相关因素。方法:采用高效液相色谱法-质谱联用技术测定伏立康唑血浆谷浓度,采用Sanger测序技术检测患儿CYP2C19基因多态性,分析年龄、性别、体质量指数、给药途径、给药剂量和CYP2C19基因多态性对伏立康唑谷浓度的影响。结果:9例患儿的伏立康唑血浆谷浓度<0.5μg·mL^(-1),26例伏立康唑谷浓度>6μg·mL^(-1)。伏立康唑血浆谷浓度与患儿的年龄存在显著相关性(F=2.671,P<0.05)。静脉途径给药患儿的伏立康唑浓度剂量比结果显著高于口服途径给药的患儿(t=-2.330,P<0.05)。伏立康唑在超快代谢型患儿中的血浆谷浓度显著低于慢代谢型、中间代谢型和正常代谢型患儿[(1.84±1.47),(4.21±12.26),(2.75±1.91),(3.60±2.13)μg·mL^(-1);P<0.05]。使用伏立康唑后,患儿谷丙转氨酶、谷草转氨酶、总胆红素、血肌酐及尿素氮水平均显著高于使用前水平(P<0.05)。结论:通过监测伏立康唑血浆谷浓度并联合CYP2C19基因多态性来共同指导异基因HSCT高危患儿使用伏立康唑具有一定的临床意义。

OBJECTIVE To evaluate the distribution characteristics of voriconazole trough concentration in the treatment and prevention of fungal infection in Xinjiang Uygur children at high risk of allogeneic hematopoietic stem cell transplantation(HSCT), and to explore the related factors affecting voriconazole plasma trough concentration.METHODS High-performance liquid chromatography-mass spectrometry was used to determine the trough plasma concentration of voriconazole, and Sanger sequencing technology was used to detect the CYP2 C19 gene polymorphism in children. The effects of age, gender, body mass index, route of administration, dose and CYP2 C19 gene polymorphism on voriconazole trough concentrations were analyzed.RESULTS The plasma trough concentration of voriconazole was <0.5 μg·mL^(-1)in nine children, and 26 children had voriconazole trough concentration >6 μg·mL^(-1). There was a significant correlation between the plasma trough concentration of voriconazole and the age of children(F=2.671,P<0.05). The CDR results of voriconazole were significantly higher in children administered intravenously than those administered by oral route(t=-2.330, P<0.05). The plasma trough concentrations of voriconazole in children with ultrafast metabolizers were significantly lower than those in children with slow metabolizers, intermediate metabolizers and normal metabolizers [(1.84±1.47),(4.21±12.26),(2.75±1.91) and(3.60±2.13) μg·mL^(-1), P<0.05]. After voriconazole treatment, the levels of alanine aminotransferase, aspartate aminotransferase, total bilirubin, serum creatinine and blood urea nitrogen were significantly higher than those before treatment(P<0.05).CONCLUSION Monitoring voriconazole plasma trough concentration and combining CYP2 C19 gene polymorphism to guide the use of voriconazole in high-risk children with allogeneic HSCT has certain clinical significance.