Clinical significance of CYP2C9-status guided valproic acid therapy in children
Clinical significance of CYP2C9-status guided valproic acid therapy in children
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DOI：
10.1111/epi.13011
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发表时间：
2015-06-01
期刊：
影响因子：
5.6
通讯作者：
Monostory, Katalin
中科院分区：
文献类型：
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作者：
Budi, Tamas;Toth, Katalin;Monostory, Katalin
目的丙戊酸(VPA)引起的不良反应在儿童中有时是严重的，可能与VPA代谢的改变有关。VPA诱导的毒性既归因于母体化合物，也归因于其不饱和代谢产物，主要由细胞色素P450(CYP)2C9酶形成。因此，患者的CYP2C9状态可能是不良反应的易感性的原因，检测CYP2C9状态可能有助于改善和合理化儿童VPA治疗。方法在CYPtest组，在开始抗癫痫治疗之前对儿童进行CYP2C9状态筛查。通过鉴定缺陷的CYP2C9等位基因变异(CYP2C9*2、CYP2C9*3)和患者白细胞中当前的CYP2C9表达来评估CYP2C9状态，这反映了肝脏的CYP2C9活性。当结合CYP2C9基因分型和CYP2C9表达的结果时，可以预测患者的VPA代谢能力，并根据患者的CYP2C9状态调整VPA的剂量。比较两组患者的VPA血药浓度、血细胞计数、肝功能指标、不良反应等临床生化指标，并与常规应用VPA治疗的对照组进行比较。结果：在CYP2C9的指导下，VPA误用明显减少，VPA血药浓度超标率明显降低。在接受细胞色素P450-C9状态适应剂量的儿童中，血清碱性磷酸酶(ALP)水平和ALP异常患者的比例明显低于对照组。CPP试验组严重副作用的发生率明显降低，尤其是高氨血症，但其他一些副作用，如体重变化和嗜睡等也无法避免。了解儿科患者的CYP2C9状况有助于优化VPA的用药，避免误用引起的副作用。
ObjectivesValproic acid (VPA)-induced adverse effects, which are sometimes serious in children, can be associated with alterations in VPA metabolism. VPA-evoked toxicity is attributed to both the parent compound and its unsaturated metabolites, primarily formed by the cytochrome P450 (CYP)2C9 enzyme. Thus, patients' CYP2C9-status may account for the predisposition to adverse reactions, and testing CYP2C9-status may contribute to the improvement and rationalization of VPA therapy in children.MethodsIn the CYPtest group, children's CYP2C9-status was screened before initiating antiepileptic therapy. CYP2C9-status was estimated by the identification of defective CYP2C9 allelic variants (CYP2C9*2, CYP2C9*3) and current CYP2C9 expression in patients' leukocytes, which reflects hepatic CYP2C9 activities. When the results of CYP2C9 genotyping and CYP2C9 expression were combined, the patients' VPA-metabolizing capacity was predicted, and VPA dosing was adjusted to the patients' CYP2C9-status. Clinical and biochemical parameters, such as VPA serum levels, blood cell counts, liver function parameters, and adverse effects in patients of CYPtest group were compared with those of the control group treated with VPA according to conventional clinical practice.ResultsCYP2C9-guided treatment significantly reduced VPA misdosing and consequently decreased the ratio of patients out of the range of target VPA blood concentrations. In the CYPtest group of children who received CYP2C9-status adapted dose, serum alkaline phosphatase (ALP) level and the ratio of patients with abnormal ALP levels were substantially lower than in the control group. The incidence of serious side effects, notably hyperammonemia, was reduced in the CYPtest group; however, some other side effects, such as weight changes and somnolence, could not be avoided.SignificanceThe knowledge of pediatric patients' CYP2C9-status can contribute to the optimization of VPA dosing and to the avoidance of misdosing-induced side effects.