血液系统恶性肿瘤患者伏立康唑谷浓度高变异性分析

目的 探讨影响血液系统恶性肿瘤患者伏立康唑谷浓度变异的潜在因素。方法 回顾性地收集2015年11月至2017年9月期间进行伏立康唑治疗药物监测的血液系统恶性肿瘤患者的病史信息、临床资料、用药情况和实验室数据等，分析人口学、生理病理、合并用药、CYP2C19基因型等与标准化谷浓度的相关性。结果 研究最终纳入176例患者241例监测数据，结果显示血液系统恶性肿瘤患者伏立康唑标准化谷浓度存在较大变异（范围从0.38-14.72 mg·L-1）。单因素和多因素Logistic回归分析结果提示，CYP2C19 *1/*1（快代谢型）是标准化谷浓度<1.0 mg·L-1的危险因素（OR: 4.445, 95% CI: 1.514–38.449, P: 0.015）；C反应蛋白（OR: 2.377, 95% CI: 1.116, 5.063, P: 0.025）、合并使用奥美拉唑（OR: 4.537, 95% CI: 1.716, 14.637, P: 0.018）及CYP2C19 *2/*2，*2/*3和*3/*3（慢代谢型）（OR: 10.199, 95% CI: 2.516, 21.342, P: 0.001）是VCZ标准化谷浓度> 5.5 mg·L-1的危险因素。结论 血液系统恶性肿瘤患者伏立康唑谷浓度变异度高，影响因素多。CYP2C19基因型、合用奥美拉唑、以及患者炎症水平可能是治疗时需考虑的因素。

Analysis of High Variability of Voriconazole Trough Concentration in Patients with Haematological Malignancies

OBJECTIVE To explore the potential factors associated with the variability of voriconazole trough concentration in patients with haematological malignancies. METHODS Medical history, clinical data, medication status and laboratory data of patients with haematological malignancies who underwent voriconazole therapeutic drug monitoring were retrospectively collected from November 2015 to September 2017. The correlation between normalized trough concentrations and demographics, physiological and pathology, drug combination, and CYP2C19 genotype was analyzed. RESULTS A total of 176 patients, 241 cases of monitoring data were included in the study. The results showed that voriconazole trough concentration in patients with haematological malignancies had high variability. Univariate and multivariate Logistic analysis suggested the CYP2C19*1/*1(extensive metabolizer) increased the risk of normalized trough concentration <1.0 mg·L^-1(OR:4.445, 95%CI:1.514-38.449, P=0.015); While C-reactive protein(OR:2.377, 95%CI:1.116-5.063, P=0.025), combined with omeprazole(OR:4.537, 95%CI:1.716-14.637, P=0.018), and CYP2C19*2/*2, *2/*3 and *3/*3 (poor metabolizer)(OR:10.199, 95%CI:2.516-21.342, P=0.001) were risk factors of normalized trough concentration >5.5 mg·L^-1. CONCLUSION Voriconazole trough concentration in patients with haematological malignancies has high variability and complicated factor. CYP2C19 genotype, concomitant with omeprazole, and inflammation should be considered in the treatment.