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Effects of CYP2C19 genetic polymorphisms on the pharmacokinetics of lacosamide in Korean patients with epilepsy

拉考沙胺 CYP2C19型 药代动力学 药效学 医学 药理学 药物遗传学 内科学 不利影响 癫痫 基因型 胃肠病学 单核苷酸多态性 CYP2D6型 SLCO1B1型 静脉血 生物 细胞色素P450 新陈代谢 遗传学 基因 精神科
作者
Seon‐Jae Ahn,Jaeseong Oh,Do‐Yong Kim,Hyoshin Son,Sungeun Hwang,Hye‐Rim Shin,Eun Young Kim,Han Sang Lee,Woo‐Jin Lee,Jangsup Moon,Soon‐Tae Lee,Keun‐Hwa Jung,Kyung‐Il Park,Ki‐Young Jung,SeungHwan Lee,Kyung‐Sang Yu,Kon Chu,Sang Kun Lee
出处
期刊:Epilepsia [Wiley]
卷期号:63 (11): 2958-2969 被引量:10
标识
DOI:10.1111/epi.17399
摘要

Many pharmacokinetic studies of lacosamide (LCM) have been reported, but no large-scale clinical study has been conducted on genetic polymorphisms that affect the metabolism of LCM. Therefore, we designed a pharmacogenetic study of LCM to explore the effect of genetic polymorphisms on serum LCM concentration. We evaluated the pharmacodynamic characteristics of LCM, including clinical efficacy and toxicity.Adult patients with epilepsy who received LCM at Seoul National University Hospital were enrolled. Blood samples were obtained from 115 patients taking LCM for more than 1 month with unchanged doses and were used to analyze the serum LCM concentration, the concentration/dose (C/D) ratio and the single nucleotide polymorphisms (SNPs) of the cytochrome P450 (CYP)2C9 and CYP2C19 genes. In addition, clinical information-including efficacy, toxicity, and concomitant drugs-was collected.The serum LCM concentration showed a linear correlation with the daily dose (r = .66, p < .001). In genetic analysis, 43 patients (38.7%) were extensive metabolizers (EMs), 51 (45.9%) were intermediate metabolizers (IMs), and 17 (15.3%) were poor metabolizers (PMs). In the group comparison, mean serum concentrations and the C/D ratio showed significant differences between the three groups (p = .01 and p < .001, respectively). The C/D ratios of IM (27.78) and PM (35.6) were 13% and 39% higher than those of EM (25.58), respectively. In the pharmacodynamic subgroup analysis, patients in the ineffective LCM group had significantly lower serum concentrations (6.39 ± 3.25 vs. 8.44 ± 3.68 μg/ml, p = .024), whereas patients with adverse events had higher serum concentrations than those without adverse events (11.03 ± 4.32 vs. 7.4 ± 3.1 μg/ml, p < .001). Based on this, we suggest a reference range for LCM in the Korean population (6-9 μg/ml).Genetic polymorphisms of the CYP2C19 gene affect the serum LCM concentration. Because efficacy and toxicity are apparently related to serum LCM levels, the genetic phenotype of CYP2C19 should be considered when prescribing LCM for patients with epilepsy.
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