Pharmacogenomic Variability of Oral Baclofen Clearance and Clinical Response in Children With Cerebral Palsy.
Pharmacogenomic Variability of Oral Baclofen Clearance and Clinical Response in Children With Cerebral Palsy.
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DOI：
10.1016/j.pmrj.2017.08.441
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Leeder JS
中科院分区：
文献类型：
--
作者：
McLaughlin MJ;He Y;Brunstrom-Hernandez J;Thio LL;Carleton BC;Ross CJD;Gaedigk A;Lewandowski A;Dai H;Jusko WJ;Leeder JS
药物基因组学变异性可导致药代动力学和临床反应的差异。尚未对具有遗传变异的小儿脑瘫（CP）患者进行这些潜在差异的研究。确定口服巴氯芬清除率和临床反应变异的遗传来源。确定口服巴氯芬清除率和临床反应变异性的药物基因组学附加研究。基于学术小儿脑瘫诊所的多中心研究。49例参与口服巴氯芬药代动力学/药效学（PK/PD）研究的CP患者。在PK/PD试验的53名参与者中，49人接受了涉及药物吸收，分布，代谢和排泄的307个关键基因和4，535个单核苷酸多态性（SNP）的遗传分析。通过单变量分析确定巴氯芬处置（体重校正和异速生长比例清除率）的基因型和表型与临床终点（R1痉挛性抓地力改善的平均腿筋改良Tardieu量表（MTS）评分较基线的改善）之间的相关性，并通过错误发现率（FDR）校正多重检验。主要结果测量是口服巴氯芬的异速生长比例清除率的基因型和表型变异性以及与基线相比MTS角的变化。在对数据进行单变量分析后，ABCC 9的SNP（rs 11046232，杂合子AT与参考TT基因型）与口服巴氯芬清除率增加2倍相关（AT基因型的平均值为0.51 ±标准差0.05 L/hr/kg，TT基因型的平均值为0.25 ± 0.07 L/hr/kg，校正后p<0.001）。MTS在具有SNPs ABCC 12、SLC 28 A1和PPARD的等位基因变体中的临床应答与痉挛减少相关。影响口服巴氯芬清除率的ABCC 9基因变异强调了继续研究遗传多态性的必要性，以更好地表征CP儿童的可变药物应答。ABCC 12、SLC 28 A1和PPARD的单核苷酸多态性与不同的反应相关，这需要进一步研究以确定它们对痉挛的影响。
Pharmacogenomic variability can contribute to differences in pharmacokinetics and clinical responses. Pediatric patients with cerebral palsy (CP) with genetic variations have not been studied for these potential differences. To determine the genetic sources of variation in oral baclofen clearance and clinical responses. Pharmacogenomic add-on study to determine variability in oral baclofen clearance and clinical responses. Multicenter study based in academic pediatric cerebral palsy clinics. 49 patients with CP who had participated in an oral baclofen Pharmacokinetic/Pharmacodynamic (PK/PD) study. From 53 participants in a PK/PD trial, 49 underwent genetic analysis of 307 key genes and 4,535 single-nucleotide polymorphisms (SNPs) involved in drug absorption, distribution, metabolism and excretion. Associations between genotypes and phenotypes of baclofen disposition (weight-corrected and allometrically scaled clearance) and clinical endpoints (improvement from baseline in mean hamstring Modified Tardieu Scale (MTS) scores from baseline for improvement of R1 spastic catch) were determined by univariate analysis with correction for multiple testing by false discovery rate (FDR). Primary outcome measures were the genotypic and phenotypic variability of oral baclofen in allometrically scaled clearance and change in the MTS angle compared to baseline. After univariate analysis of the data, the SNP of ABCC9 (rs11046232, heterozygous AT vs. the reference TT genotype) was associated with a 2-fold increase in oral baclofen clearance (Mean 0.51 ± Standard Deviation 0.05 L/hr/kg for the AT genotype vs. 0.25 ± 0.07 L/hr/kg for the TT genotype, adjusted p<.001). Clinical responses were associated with decreased spasticity by MTS in allelic variants with SNPs ABCC12, SLC28A1, and PPARD. Genetic variation in ABCC9 impacting oral baclofen clearance highlights the need for continued studies of genetic polymorphisms to better characterize variable drug response in children with CP. Single nucleotide polymorphisms in ABCC12, SLC28A1, and PPARD were associated with varied responses, which warrants further investigation to determine their effect on spasticity.
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