Bolcato Léa, Khouri Charles, Veringa Anette, Alffenaar Jan Willem C, Yamada Takahiro, Naito Takafumi, Lamoureux Fabien, Fonrose Xavier, Stanke-Labesque Françoise, Gautier-Veyret Elodie
Laboratory of Pharmacology, Pharmacogenetics and Toxicology, Grenoble Alpes University Hospital, 38000 Grenoble, France.
Pharmacovigilance Unit, Grenoble Alpes University Hospital, 38000 Grenoble, France.
J Clin Med. 2021 May 13;10(10):2089. doi: 10.3390/jcm10102089.
Few studies have simultaneously investigated the impact of inflammation and genetic polymorphisms of cytochromes P450 2C19 and 3A4 on voriconazole trough concentrations. We aimed to define the respective impact of inflammation and genetic polymorphisms on voriconazole exposure by performing individual data meta-analyses. A systematic literature review was conducted using PubMed to identify studies focusing on voriconazole therapeutic drug monitoring with data of both inflammation (assessed by C-reactive protein level) and the pharmacogenomics of cytochromes P450. Individual patient data were collected and analyzed in a mixed-effect model. In total, 203 patients and 754 voriconazole trough concentrations from six studies were included. Voriconazole trough concentrations were independently influenced by age, dose, C-reactive protein level, and both cytochrome P450 2C19 and 3A4 genotype, considered individually or through a combined genetic score. An increase in the C-reactive protein of 10, 50, or 100 mg/L was associated with an increased voriconazole trough concentration of 6, 35, or 82%, respectively. The inhibitory effect of inflammation appeared to be less important for patients with loss-of-function polymorphisms for cytochrome P450 2C19. Voriconazole exposure is influenced by age, inflammatory status, and the genotypes of both cytochromes P450 2C19 and 3A4, suggesting that all these determinants need to be considered in approaches of personalization of voriconazole treatment.
很少有研究同时调查炎症以及细胞色素P450 2C19和3A4的基因多态性对伏立康唑谷浓度的影响。我们旨在通过进行个体数据荟萃分析来确定炎症和基因多态性对伏立康唑暴露的各自影响。使用PubMed进行了系统的文献综述，以识别专注于伏立康唑治疗药物监测且有炎症数据（通过C反应蛋白水平评估）和细胞色素P450药物基因组学数据的研究。在混合效应模型中收集并分析个体患者数据。总共纳入了来自六项研究的203名患者和754个伏立康唑谷浓度数据。伏立康唑谷浓度分别受年龄、剂量、C反应蛋白水平以及细胞色素P450 2C19和3A4基因型的独立影响，这些因素单独考虑或通过综合基因评分考虑。C反应蛋白每增加10、50或100 mg/L，伏立康唑谷浓度分别增加6%、35%或82%。对于细胞色素P450 2C19功能缺失多态性的患者，炎症的抑制作用似乎不那么重要。伏立康唑暴露受年龄、炎症状态以及细胞色素P450 2C19和3A4基因型的影响，这表明在伏立康唑治疗个体化方法中需要考虑所有这些决定因素。
