Division of Rehabilitation Medicine, Children's Mercy-Kansas City, 2401 Gillham Road, Kansas City, MO 64108; Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy, Kansas City, MO.
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of Buffalo, Buffalo, NY.
PM R. 2018 Mar;10(3):235-243. doi: 10.1016/j.pmrj.2017.08.441. Epub 2017 Sep 1.
Pharmacogenomic variability can contribute to differences in pharmacokinetics and clinical responses. Pediatric patients with cerebral palsy 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.
A total of 49 patients with cerebral palsy who had participated in an oral baclofen pharmacokinetic/pharmacodynamic study.
Of 53 participants in a pharmacokinetic/pharmacodynamic trial, 49 underwent genetic analysis of 307 key genes and 4535 single-nucleotide polymorphisms 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 scores from baseline for improvement of R1 spastic catch) were determined by univariate analysis with correction for multiple testing by false discovery rate.
Primary outcome measures were the genotypic and phenotypic variability of oral baclofen in allometrically scaled clearance and change in the Modified Tardieu Scale angle compared to baseline.
After univariate analysis of the data, the SNP of ABCC9 (rs11046232, heterozygous AT versus the reference TT genotype) was associated with a 2-fold increase in oral baclofen clearance (mean 0.51 ± standard deviation 0.05 L/h/kg for the AT genotype versus 0.25 ± 0.07 L/h/kg for the TT genotype, adjusted P < .001). Clinical responses were associated with decreased spasticity by Modified Tardieu Scale in allelic variants with SNPs ABCC12, SLC28A1, and PPARD.
Genetic variation in ABCC9 affecting oral baclofen clearance highlights the need for continued studies of genetic polymorphisms to better characterize variable drug response in children with cerebral palsy. 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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药物基因组学的变异性可导致药代动力学和临床反应的差异。患有脑瘫的儿科患者尚未对这些潜在差异进行基因变异的研究。
确定口服巴氯芬清除率和临床反应的遗传来源。
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。
基于学术性儿科脑瘫诊所的多中心研究。
总共 49 名参加过口服巴氯芬药代动力学/药效学研究的脑瘫患者。
在药代动力学/药效学试验的 53 名参与者中，49 名接受了 307 个关键基因和 4535 个单核苷酸多态性的基因分析，这些基因涉及药物吸收、分布、代谢和排泄。通过单变量分析确定基因型与巴氯芬处置（体重校正和比例清除率）表型和临床终点（基线时平均比目鱼肌改良 Tardieu 量表评分的改善，以改善 R1 痉挛性捕获）之间的关联，并通过错误发现率对多重检验进行校正。
主要观察指标是比例清除率的口服巴氯芬的基因型和表型变异性，以及与基线相比改良 Tardieu 量表角度的变化。
对数据进行单变量分析后，ABCC9 的 SNP(rs11046232，杂合 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 0.51±标准偏差 0.05 L/h/kg 与 TT 基因型的 0.25±0.07 L/h/kg 相比，调整 P<.001)。临床反应与 ABCC12、SLC28A1 和 PPARD 中 SNP 的等位变体的改良 Tardieu 量表的痉挛性降低相关。
ABCC9 影响口服巴氯芬清除率的遗传变异突出表明需要继续研究遗传多态性，以更好地描述脑瘫儿童的药物反应变异性。ABCC12、SLC28A1 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。
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