Lamoureux Fabien, Duflot Thomas, Woillard Jean-Baptiste, Metsu David, Pereira Tony, Compagnon Patricia, Morisse-Pradier Hélène, El Kholy Mona, Thiberville Luc, Stojanova Jana, Thuillez Christian
Department of Pharmacology and Toxicology, University Hospital, Rouen, France; INSERM U1096, University of Rouen, School of Medicine, Rouen, France.
Department of Pharmacology and Toxicology, University Hospital, Rouen, France; INSERM U1096, University of Rouen, School of Medicine, Rouen, France.
Int J Antimicrob Agents. 2016 Feb;47(2):124-31. doi: 10.1016/j.ijantimicag.2015.12.003. Epub 2015 Dec 21.
Voriconazole (VCZ) use is limited by its narrow therapeutic range and significant interpatient variability in exposure. This study aimed to assess (i) the impact of CYP2C19 genotype on VCZ exposure and (ii) the doses required to achieve the therapeutic range in adult patients with invasive fungal infections (IFIs). Therapeutic drug monitoring (TDM) of VCZ, based on trough concentration measurement, and CYP2C19 genotyping were used to guide VCZ dosing in Caucasian patients with IFIs. The two common polymorphisms in Caucasians (CYP2C192 and 17), associated with decreased or increased CYP2C19 activity, respectively, were correlated with the daily VCZ dose, pharmacokinetic parameters and concentration-to-dose ratio. In total, 111 trough concentration measurements from 35 genotyped patients were analysed using linear mixed-effect models. The mean VCZ doses required to achieve target concentrations were significantly higher in CYP2C1917 carriers compared with CYP2C191/1 individuals (P<0.001): 2.57±0.25mg/kg twice daily in CYP2C191/*1 patients versus 3.94±0.39mg/kg and 6.75±0.54mg/kg in *1/17 and 17/17 patients, respectively. In addition, exposure to VCZ correlated with the CYP2C1917 variant. Indices of exposure for CYP2C192 carriers were in line with the functional effect of this polymorphism compared with CYP2C191/1 individuals, however comparisons of doses required to achieve target concentrations were not statistically different. The CYP2C1917 allele predicted both VCZ exposure and dose required to achieve effective and non-toxic concentrations. CYP2C19 genotyping appears useful to guide VCZ initial dosing when coupled with TDM and to explain subtherapeutic concentrations frequently observed in clinical practice.
伏立康唑（VCZ）的使用因其狭窄的治疗窗和患者间显著的暴露差异而受到限制。本研究旨在评估（i）CYP2C19基因分型对VCZ暴露的影响，以及（ii）侵袭性真菌感染（IFI）成年患者达到治疗窗所需的剂量。基于谷浓度测量的VCZ治疗药物监测（TDM）和CYP2C19基因分型被用于指导白种人IFI患者的VCZ给药。白种人中两种常见的多态性（CYP2C192和17），分别与CYP2C19活性降低或增加相关，与每日VCZ剂量、药代动力学参数以及浓度-剂量比相关。总共对35例基因分型患者的111次谷浓度测量值使用线性混合效应模型进行了分析。与CYP2C191/1个体相比，CYP2C1917携带者达到目标浓度所需的平均VCZ剂量显著更高（P<0.001）：CYP2C191/1患者为每日2次、每次2.57±0.25mg/kg，而1/17和17/17患者分别为3.94±0.39mg/kg和6.75±0.54mg/kg。此外，VCZ暴露与CYP2C1917变异相关。与CYP2C191/1个体相比，CYP2C192携带者的暴露指标与该多态性的功能效应一致，然而达到目标浓度所需剂量的比较在统计学上无差异。CYP2C1917等位基因可预测VCZ暴露以及达到有效和无毒浓度所需的剂量。当与TDM结合时，CYP2C19基因分型似乎有助于指导VCZ初始给药，并解释临床实践中经常观察到的亚治疗浓度。
