Voriconazole plasma concentrations in immunocompromised pediatric patients vary by CYP2C19 diplotypes
Voriconazole plasma concentrations in immunocompromised pediatric patients vary by CYP2C19 diplotypes
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DOI：
10.2217/pgs.14.53
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发表时间：
2014-06-01
期刊：
影响因子：
2.1
通讯作者：
Relling, Mary V.
中科院分区：
文献类型：
--
作者：
Hicks, J. Kevin;Crews, Kristine R.;Relling, Mary V.
目的：我们的目的是描述伏立康唑浓度与儿童癌症患者CYP2C19二倍型之间的关系，包括CYP2C19*17功能获得等位基因纯合的儿童。材料与方法：采用线性混合效应模型比较33例（年龄1-19岁）患者CYP2C19二倍型患者伏立康唑剂量校正谷浓度（n = 142）。伏立康唑药代动力学采用Michaelis-Menten消去双室模型描述。结果：年龄（p = 0.05）和CYP2C19二倍型（p = 0.002）与伏立康唑浓度相关。CYP2C19*17本合子从未达到治疗浓度，校正后的伏立康唑剂量浓度（中位数：0.01 μ g/ml/mg/kg, p = 0.02）低于CYP2C19*1纯合子（中位数：0.07 μ g/ml/mg/kg）。模型显示，较高的剂量可能在年龄较小的儿童和CYP2C19*171*17二倍型的儿童中产生治疗浓度。结论：年龄较小和CYP2C19功能获得等位基因的存在与亚治疗伏立康唑浓度相关。基于年龄和CYP2C19状态的起始剂量可以增加获得治疗性伏立康唑暴露的患者数量。
Aim: Our objective was to describe the association between voriconazole concentrations and CYP2C19 diplotypes in pediatric cancer patients, including children homozygous for the CYP2C19*17 gain-of-function allele. Materials & methods: A linear mixed effect model compared voriconazole dose corrected trough concentrations (n = 142) among CYP2C19 diplotypes in 33 patients (aged 1-19 years). Voriconazole pharnnacokinetics was described by a two-compartment model with Michaelis-Menten elimination. Results: Age (p = 0.05) and CYP2C19 diplotype (p = 0.002) were associated with voriconazole concentrations. CYP2C19*17 honnozygotes never attained therapeutic concentrations, and had lower dose corrected voriconazole concentrations (median: 0.01 mu g/ml/mg/kg; p = 0.02) than CYP2C19*1 homozygotes (median: 0.07 mu g/ml/mg/kg). Modeling indicates that higher doses may produce therapeutic concentrations in younger children and in those with a CYP2C19*171*17 diplotype. Conclusion: Younger age and the presence of CYP2C19 gain-of-function alleles were associated with subtherapeutic voriconazole concentrations. Starting doses based on age and CYP2C19 status could increase the number of patients achieving therapeutic voriconazole exposure.