成人伏立康唑个体化用药监测分析

Individualized medication monitoring of voriconazole in adults

摘要:

目的 基于《伏立康唑个体化用药指南》中伏立康唑的谷浓度与抗感染的疗效、肝脏毒性相关性仅以一个中等质量的证据来评判，不能很好满足临床需求。本论文将建立动态监测成人住院患者的伏立康唑谷浓度变化，力求探究谷浓度与疗效、不良反应的相关性。方法 收集使用伏立康唑治疗的成人患者63例，共107份血液标本，采用酶免方法动态监测伏立康唑的药物谷浓度，观察患者的用药疗效、有无不良反应，剖析伏立康唑谷浓度与临床指标的相关性。结果 ①使用常规剂量伏立康唑治疗后，62/107（57.9%）血液标本的伏立康唑谷浓度在0.5~5.0 μg/mL，均数为2.7 μg/mL；4/107（3.7%）血液标本的谷浓度<0.5 μg/mL，均数为0.3 μg/mL；41/107（38.4%）血液标本的谷浓度>5.0 μg/mL，中位数为8.7 μg/mL。②谷浓度<0.5 μg/mL组、谷浓度≥0.5 μg/mL组治疗有效的比率分别为50.0%、74.5%，但2组差异无统计学意义（P=0.624）。提高1例谷浓度<0.5 μg/mL且治疗无效的患者剂量，使谷浓度达到有效浓度，感染症状获得改善。③10例（15.8%）发生不良反应，谷浓度>5.0 μg/mL的患者与谷浓度≤5.0 μg/mL的患者不良反应发生率分别为18.2%、14.6%，主要体现为肝功能异常。④伏立康唑谷浓度≤5.0 μg/mL的患者组与谷浓度>5.0 μg/mL的患者组碱性磷酸酶（alkaline phosphatase，ALP）、谷氨酰转肽酶（glutamyl transpeptidase，GGT）差异有统计学意义（P<0.05），当谷浓度>5.0 μg/mL时，抗感染治疗后，降钙素原（procalcitonin，PCT）明显降低（P<0.05）。结论 伏立康唑血药浓度个体间差异较大，必须规律监测谷浓度。伏立康唑谷浓度与肝功能、感染指标相关，可能要加大人群数或者在CYP2C19基因检测支持下来观察谷浓度与疗效、不良反应的相关性。

Abstract:

Objective According to the trough concentration，anti-infective efficacy，and hepatotoxicity of voriconazole in Individualized Medication of Voriconazole：A Practice Guideline of the Division of Therapeutic Drug Monitoring， the judgment based on medium-quality evidence cannot meet clinical needs. This article will perform dynamic monitoring of the trough concentration of voriconazole in adult inpatients to investigate the association of trough concentration with therapeutic efficacy and adverse reactions.Methods A total of 107 blood samples were collected from 63 adult patients who were treated with voriconazole， and enzyme immunoassay was used for dynamic monitoring of the trough concentration of voriconazole. The patients were observed in terms of treatment outcome and adverse reactions，and the correlation of the trough concentration of voriconazole with clinical indices was analyzed.Results After treatment with voriconazole at the conventional dose，the trough concentration of voriconazole was 0.5-5.0 μg/mL in 57.9%（62/107） of the samples，with a averge concentration of 2.7 μg/mL；the trough concentration of voriconazole was <0.5 μg/mL in 3.7%（4/107） of the samples，with a averge concentration of 0.3 μg/mL；the trough concentration of voriconazole was >5.0 μg/mL in 38.4% （41/107） of the samples，with a median concentration of 8.7 μg/mL. The patients with a trough concentration of <0.5 μg/mL had a response rate of 50.0%，while those with a trough concentration of ≥0.5 μg/mL had a response rate of 74.5%，and there was no significant difference between the two groups（P=0.624）. The dose was increased for one patient who had a trough concentration of <0.5 μg/mL and had no response to treatment，and the symptoms of infection were improved after effective trough concentration was reached. Adverse reactions were observed in 10 patients（15.8%）， and the incidence rate of adverse reactions was 18.2% in patients with a trough concentration of >5.0 μg/mL and 14.6% in those with a trough concentration of ≤5.0 μg/mL， with the main adverse reaction of abnormal liver function. There were significant differences in alkaline phosphatase and gamma-glutamyl transpeptidase between the patients with a trough concentration of >5.0 μg/mL and those with a trough concentration of ≤5.0 μg/mL（P<0.05），and when the trough concentration of voriconazole was >5.0 μg/mL，there was a significant reduction in procalcitonin after anti-infective therapy（P<0.05）.Conclusion There is a large difference in the plasma concentration of voriconazole between individuals， and its trough concentration must be monitored regularly. The trough concentration of voriconazole is associated with liver function parameters and infection indicators， and it may be necessary to increase sample size or perform CYP2C19 genetic testing to observe the association of trough concentration with therapeutic efficacy and adverse reactions.