伏立康唑在肝硬化患者中的治疗药物监测及用药安全性评价

目的:探讨伏立康唑在肝硬化患者中的血药谷浓度(C_min)的分布特征及影响浓度变异的因素,并对其进行用药安全性评价。方法:患者使用的维持剂量有减半维持剂量(A组)和标准维持剂量(B组),采用HPLC法测定伏立康唑血药浓度。收集伏立康唑用药相关信息,采用多元线性回归探讨影响伏立康唑C_min的因素。结果:本研究共监测了53例肝硬化病患者的74个血药浓度。A组患者伏立康唑C_min为(4.02±1.94)μg·mL^-1,B组患者伏立康唑C_min为(6.89±4.57)μg·mL^-1。其中A组中有30.8%的C_min高于治疗窗上限,B组有63.4%的C_min高于治疗窗上限。多元线性回归分析结果表明A组患者中伏立康唑C_min与白蛋白值、INR值、合并使用肝毒性药物和CYP2C19抑制剂具有显著相关性。研究中并没有发现对B组血药浓度有影响的因素。伏立康唑在A组和B组中的不良反应发生率分别为11.4%和38.9%。结论:减半维持剂量在肝硬化患者中仍具有较高的血药浓度。肝硬化患者使用伏立康唑应密切监测血药浓度,从而保证伏立康唑治疗的安全性和有效性。

Voriconazole therapeutic drug monitoring and safety in patients with liver cirrhosis

OBJECTIVE To investigate the distribution characteristics of trough plasma concentration (Cmin) of voriconazole in patients with liver cirrhosis and the factors affecting concentration variation,and to evaluate its medication safety.METHODS Liver cirrhosis patients who received the halved maintenance dose (group A) and the recommended voriconazole maintenance dose (group B) were included.Voriconazole C_min was measured by high-performance liquid chromatography (HPLC).Data pertaining to voriconazole were collected,and multivariable linear regression models were used to investigate the effect of variables on voriconazole C_min.RESULTS A total of 74 samples were collected from 53 patients.Voriconazole C_min was 4.02±1.94 μg·mL^-1 and 6.89±4.57 μg·mL^-1 in group A and group B,respectively.The proportion of voriconazole C_min higher than supertherapeutic concentration in group A and B was 30.8% and 63.4%,respectively.Albumin,international normalized ratio,co-medication with CYP2C19 inhibitor and hepatotoxic drug had a significant effect on voriconazole C_minin group A.However,there was no covariates that associated with significant C_min of voriconazole in group A.The incidence of AEs in the group A and B was 11.4% and 38.9%,respectively.CONCLUSIONS Half-maintenance dose still has high plasma concentration in patients with liver cirrhosis.Plasma concentrations of voriconazole should be closely monitored in patients with cirrhosis to ensure the safety and efficacy of voriconazole therapy.