基于伏立康唑血药浓度监测数据的回顾性分析

Retrospective analysis of voriconazole blood concentration based on therapeutic drug monitoring

目的评估伏立康唑(VRCZ)血药浓度监测(TDM)在临床应用过程中的实用性,阐明影响VRCZ血药浓度以及引起不良反应的相关因素。方法采用回顾性队列研究的方法,收集2016年3月至2018年12月接受VRCZ TDM作为常规治疗的患者资料,提取临床数据后进行比较与分析。结果共收集到患者110例,送检样品138份。在送检样品中,VRCZ血药浓度的中位值为1.9 mg·L^(-1)(IQR 0.9~3.1 mg·L^(-1)),在治疗范围(1~5 mg·L^(-1))内的样品占67%。VRCZ中位日剂量为6.4 mg·kg^(-1) (IQR 5.9~7.5 mg·kg^(-1))。与日剂量<6 mg·kg^(-1)相比,6~7 mg·kg^(-1) (P=0.1)和≥7 mg·kg^(-1) (P=0.08)的中位VRCZ浓度略高。不同VRCZ剂型的血药浓度之间差异存在统计学意义(P <0.05)。单因素Logistic回归分析显示,没有因素可独立预测VRCZ血药浓度是否在治疗范围内。VRCZ的不良反应主要为肝毒性和视觉障碍,且VRCZ浓度是与肝毒性和视觉障碍相关的唯一独立变量。肝毒性和视觉障碍的受试者工作曲线(ROC)曲线下面积分别为0.67和0.78,最佳临界值分别为1.98 mg·L^(-1)(灵敏度75%,特定性59%)和2.47 mg·L^(-1) (灵敏度84%,特定性70%)。结论通过TDM调整VRCZ给药剂量以达到目标浓度,以减少肝毒性和视觉障碍的方法是非常实用的。

AIM To assess the clinical usefulness of therapeutic drug monitoring(TDM) of voriconazole(VRCZ) in a real-world clinical setting, and elucidate factors affecting attainment of target concentrations and causing adverse drug reactions. METHODS A retrospective cohort study was used to evaluate patients who received VRCZ TDM as part of routine care at a general hospital between March 2016 and December 2018. RESULTS VRCZ levels(n=138) were analyzed from 110 patients and 67% of the drug levels were within therapeutic range. The median VRCZ daily dose based on the actual body weight was 6.4 mg·kg^(-1)·d^(-1)(IQR 5.9–7.5 mg·kg^(-1)·d^(-1)). The median VRCZ level was 1.9 mg·L-1(IQR 0.9-3.1 mg·L^(-1)). When compared with the samples treated with dose <6 mg·kg^(-1)·d^(-1), the VRCZ trough level was slightly higher among those treated with 6-7 mg·kg^(-1)·d^(-1)(P=0.1) and ≥ 7 mg·kg^(-1)·d^(-1)(P=0.08). There was a statistically significant difference between dosage formulation and drug concentration(P < 0.05). In an univariable Logistic regression analysis, no characteristic was independently predictive of therapeutic voriconazole levels. The main reported adverse drug reactions were hepatotoxicity and visual disturbances. A significant difference in the drug concentration of VRCZ was observed between the hepatotoxicity and non-hepatotoxicity groups, and between the visual disturbances and nonvisual disturbances group. Multiple Logistic regression analyses identified the drug concentration as the only independent variable associated with hepatotoxicity and visual disturbances of VRCZ. The areas under the receiver operating characteristic(ROC) curves were 0.67 and 0.78 for hepatotoxicity and visual disturbances, respectively. The cut-off values of the drug concentration were 1.98 mg·L^(-1) for hepatotoxicity(sensitivity 75%, specificity 59%) and 2.47 mg·L^(-1) for visual disturbances(sensitivity 84%, specificity 70%). CONCLUSION Dose adjustments by TDM to achieve the target trough concentrations is useful in order to avoid hepatotoxicity and visual disturbances.