伏立康唑谷浓度在血液科患者中的分布特征及影响因素

Distribution characteristics and influencing factors of voriconazole trough concentration in hematological patients

目的:评估伏立康唑血药谷浓度测定在治疗和预防血液科患者真菌感染的分布特征,探讨CYP2C19基因型对伏立康唑谷浓度的影响。方法:本研究共纳入2017年1月至12月接受伏立康唑治疗的85例血液科患者。应用高效液相色谱法监测患者伏立康唑谷浓度,焦磷酸测序检测患者CYP2C19基因型。结果:85例患者中,共监测伏立康唑血药浓度201例。伏立康唑个体内及个体间谷浓度变异均较大(CV分别为56.6%和65.6%)。无论是治疗还是预防,不同给药剂量(剂量/体重)谷浓度<1 mg·L-1比例具有统计学差异。测定患者CYP2C19基因型,伏立康唑谷浓度的分布在快代谢和慢代谢组(P=0.002)、中间代谢和慢代谢组(P=0.031)的差异有统计学意义,快代谢和中间代谢组间的差异无统计学意义(P=0.181)。结论:伏立康唑谷浓度个体差异大,按照体重给药有助于提高其血药浓度达标率。CYP2C19基因对伏立康唑谷浓度具有一定影响,尤其是对于慢代谢型患者,建议对使用伏立康唑治疗或预防的患者进行药物浓度监测,旨为个体化给药提供依据。

Objective: To study the distribution characteristics of voriconazole trough concentration, and explore the effect of CYP2 C19 genotype on voriconazole trough concentration in hematological patients who underwent antifungal therapy with voriconazole. Methods: From January 2017 to December 2017, 85 patients with hematological diseases treated with voriconazole were included in this study. The patients’ CYP2 C19 genotype were detected by pyrosequencing, and voriconazole trough levels were quantified by high-performance liquid chromatography method. Results: A total of 201 voriconazole trough levels from 85 patients were measured. The concentrations of voriconazole had a large variation within and between individuals. The interindividual variabilities coefficient of voriconazole concentrations was 65.6%, and the maximum intraindividual variabilities was 56.6%. Regardless of treatment or prevention, the ratio of trough concentration < 1 mg·L-1 was statistically different for different doses(mg·kg-1). Based on the CYP2 C19 genotype analysis, there were significant differences of voriconazole trough levels in poor metabolizers(PMs) between extensive metabolizers(EMs)(P = 0.002) and intermediate metabolizers(IMs)(P = 0.031). However, no difference was found between IMs patients and EMs patient(P = 0.181). Conclusion: The results of our analysis indicated the large individual variabilities of voriconazole concentrations in hematological patients, calculating the dose according to the body weight can help to increase the achieved rate of the target blood concentration. The CYP2 C19 genes had the effect on the voriconazole trough concentration, especially in poor metabolizers. The serum concentration monitoring is recommended for hematological patients treated with voriconazole to achieve an ideal individual administration according to clinical practice.