CYP2C19*3位点不同基因型重症侵袭性真菌感染患者接受伏立康唑治疗时的血药浓度及疗效对比观察

Comparison of plasma concentration and efficacy in different genotypes of CYP2C19~*3 among severe IFI patients treated with usual-dose administration of voriconazole

目的观察CYP2C19*3位点不同基因型重症侵袭性真菌感染(IFI)患者接受常规剂量伏立康唑治疗时的血药浓度,并进行疗效对比。方法接受伏立康唑抗真菌治疗的重症IFI患者70例,用药第3天清晨用药前采集肘静脉血,抗凝存放。取抗凝全血,提取DNA并进行PCR扩增后,采用Sanger测序法检测CYP2C19*3位点基因型,依据测序结果将患者分为GG组、GA组、AA组。取抗凝全血,使用超高效液相色谱仪及Xevo TQS三重四级杆串联质谱仪检测患者伏立康唑血药浓度。70例患者伏立康唑常规剂量治疗1周及以上,然后评估治疗效果和不良反应,计算治疗有效率、不良反应发生率。结果70例患者中,CYP2C19*3位点GG型60例、GA型10例,未检测到AA基因型。GG组患者伏立康唑血药浓度为(3.58±2.84)mg/L,GA组为(5.80±2.16)mg/L,两组相比,P<0.05。GG组患者伏立康唑治疗有效率为55.00%(33/60),不良反应发生率为26.67%(16/60);GA组患者伏立康唑治疗有效率为90.00%(9/10),不良反应发生率为40.00%(4/10);两组伏立康唑治疗有效率相比,P<0.05;两组不良反应发生率相比,P>0.05。结论CYP2C19*3位点GA基因型重症IFI患者的伏立康唑血药浓度、治疗有效率均高于GG型重症IFI患者。

Objective To observe and compare the plasma concentration of voriconazole and its efficacy in patients who were diagnosed with severe invasive fungal infection(IFI)with different CYP2 C19*3 genotypes.Methods A total of 70 IFI patients treated with voriconazole were enrolled.Cubital venous blood was collected and was put into the ethylene diamine tetraacetic acid(EDTA)anticoagulant tubes on the early morning of the third day before giving next dosage.Genomic DNA was extracted from whole blood.Polymerase chain reaction(PCR)and Sanger sequencing were used to detect human CYP2 C19*3 genotypes.According to their genotypes of CYP2 C19*3,patients were classified into three groups:GG,GA,and AA groups.Ultra Performance Liquid Chromatography and Xevo TQS triple quadrupole tandem mass spectrometer were used to detect blood concentration of voriconazole.All 70 patients were given conventional dosage administration for at least one week.The therapeutic effects and adverse reaction were evaluated,and the therapeutic efficiency rate and incidence of adverse reaction were calculated.Results Among 70 IFI patients,there were 60 patients with CYP2 C19*3 GG genotype and 10 patients with CYP2 C19*3 GA genotype but there was no CYP2 C19*3 AA genotype.The plasma concentration of voriconazole for patients with GA genotype[(5.80±2.16)mg/L]was higher than for those with GG genotype[(3.58±2.84)mg/L].There was significant difference in the plasma concentration of voriconazole between the groups with GG genotype and GA genotype(P<0.05).For patients with GG genotype,the rate of therapeutic efficiency was 55%(33/60),and the incidence of adverse reaction was 26.67%(16/60).For patients with GA genotype,the rate of therapeutic efficiency was 90%(9/10),and the incidence of adverse reaction was 40%(4/10).There was significant difference in the rate of therapeutic efficiency between the two groups(P<0.05),but there was no significant difference between the two groups in the incidence of adverse reaction(P>0.05).Conclusion Plasma concentration of voriconazole and therapeutic efficiency rate are higher in patients with CYP2 C19*3 GA genetype than in patients with CYP2 C19*3 GG genotype.