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Precision Medicine in Pediatric Rehabilitation - Variability in Gabapentin Exposure

儿科康复中的精准医学 - 加巴喷丁暴露量的变异性

基本信息

批准号：
10676082
负责人：
Matthew McLaughlin
金额：
$ 16.75万
依托单位：
CHILDREN'S MERCY HOSP (KANSAS CITY, MO)
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-03 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10676082
关键词：
Address Adopted Adverse event Age Amino Acid Transporter Appearance Baclofen Blood Blood - brain barrier anatomy Calcium Channel Carrier Proteins Cell Line Cell model Cells Cerebral Palsy Cerebrospinal Fluid Child Childhood Clinical Code Complementary DNA Consent Data Diabetic Neuropathies Disease Dorsal Dose Drug Exposure Drug Interactions Drug Kinetics Drug Prescriptions Embryo Future Gender Genes Genetic Genomics Genotype Goals Grant Human In Vitro Individual Individual Differences Injury Kidney Kinetics Knowledge Label Levodopa Light Liquid Chromatography Location Medical center Medication Management Membrane Transport Proteins Methodology Modeling Oral Pain Pain management Participant Patients Peripheral Pharmaceutical Preparations Pharmacogenomics Physical Medicine Plasma Population Proteins Provider Quality of life Radiolabeled Recommendation Rehabilitation therapy Research Rhizotomy procedure Role Sampling Single Nucleotide Polymorphism Site Spinal Cord Spinal Ganglia Spinal cord injury Stroke System Therapeutic Intervention Time Transfection Variant Weight Work aged appropriate dose blood-brain barrier crossing care seeking cohort design disability effective therapy exome sequencing functional disability functional improvement gabapentin gene interaction genetic variant improved kidney cell medication administration neurological rehabilitation non-opioid analgesic pain reduction painful neuropathy patient population pediatric patients physically handicapped precision medicine pregabalin receptor rehabilitation research response somatosensory spasticity support tools tandem mass spectrometry theories uptake voltage

项目摘要

PROJECT SUMMARY Although gabapentin is the most commonly prescribed medication for patients with neuropathic pain, the high level of variability in reduction in pain limits effective treatment of pain. Work products from this grant would allow the formation of a model-informed dosing strategy for this disorder. This research will have a lasting impact on the way in which drugs are prescribed to pediatric patients with disabilities. Medications which require transport across the blood-brain barrier (BBB) frequently require transport to reach the cerebrospinal fluid (CSF). The gene SLC7A5 encodes for a light-chain protein (LAT1) that forms a heterodimer with the a heavy chain protein CD98hc (encoded by SLC3A2) to create a membrane transport protein referred to as the L-type amino acid transporter-1 (LAT1). 21 Previous in vitro studies have shown that this transporter is one of the primary mechanisms of gabapentin transport across the BBB. This transporter is also the confirmed or theorized transporter of several other commonly prescribed medications frequently prescribed by rehabilitation providers. Determining the variability in the amount of gabapentin a patient has in their plasma (systemic exposure) and the amount that crosses the blood-brain-barrier (BBB) (central exposure) is significant to optimally determine the most appropriate dose for each individual child (AIM1). The overall goal of my research strategy is to identify factors influencing variability in central exposure (cerebrospinal fluid) in pediatric patients with CP. AIM 1 investigates the amount of central exposure by determining the amount of gabapentin that crosses the BBB. A secondary portion of AIM 1 addresses the impact of the SCL7A5 gene (LAT1 transporter) by performing whole- exome sequencing to evaluate the SLC7A5 gene and genotyping of selected single-nucleotide polymorphisms in the intronic region of the LAT1 transporter. AIM 2 is divided into two sub-aims using similar methodology. The first sub-aim evaluates the impact of concurrently administered medications that also utilize the LAT1 transporter using a cell line model that is transfected with the SLC7A5 gene to evaluate potential drug-drug interactions with commonly prescribed medications in rehabilitation medicine, specifically levodopa, baclofen, and pregabalin. The second sub-aim of AIM 2 involved transfection of genetic variants of the LAT1 transporter to determine the impact of coding region changes to the function of this transporter. These variants may be informed by the whole-exome sequencing variants found in AIM 1. Both of these independent but complementary AIMs allows for data that will be incorporated within future decision support tools to more appropriate anticipate what dose of gabapentin is needed to reach a desired level of exposure and, subsequently, a desired level of clinical response (neuropathic pain reduction).

项目概要尽管加巴喷丁是神经性疼痛患者最常用的处方药物，但其高治疗率疼痛减轻的可变性水平限制了疼痛的有效治疗。这笔赠款的工作成果将允许针对这种疾病形成基于模型的给药策略。这项研究将对为残疾儿科患者开药的方式。需要穿过血脑屏障 (BBB) 的药物通常需要运输才能到达脑脊液（CSF）。基因 SLC7A5 编码轻链蛋白 (LAT1)，该蛋白形成带有重链蛋白 CD98hc（由 SLC3A2 编码）的异二聚体，以创建膜转运蛋白质称为 L 型氨基酸转运蛋白 1 (LAT1)。 21 先前的体外研究表明该转运蛋白是加巴喷丁跨血脑屏障转运的主要机制之一。这个运输机是也是几种其他常用药物的已证实或理论上的转运体由康复服务提供者规定。确定患者血浆中加巴喷丁含量的变异性（全身暴露）和穿过血脑屏障 (BBB)（中心暴露）的量对于最佳确定每个儿童最合适的剂量 (AIM1)。我的研究策略的总体目标是确定影响 CP 儿科患者中心暴露（脑脊液）变异性的因素。目标1 通过测定穿过血脑屏障的加巴喷丁的量来研究中枢暴露的量。一个 AIM 1 的次要部分通过执行整体处理来解决 SCL7A5 基因（LAT1 转运蛋白）的影响外显子组测序评估 SLC7A5 基因和选定单核苷酸多态性的基因分型位于 LAT1 转运蛋白的内含子区域。 AIM 2 使用类似的方法分为两个子目标。第一个子目标评估的影响同时施用的药物也利用 LAT1 转运蛋白，使用细胞系模型转染 SLC7A5 基因以评估潜在的药物与常用处方药物之间的相互作用康复医学中的药物，特别是左旋多巴、巴氯芬和普瑞巴林。第二个子目标 AIM 2 涉及 LAT1 转运蛋白基因变体的转染，以确定编码区的影响该转运蛋白的功能发生变化。这些变异可能是通过全外显子组测序得知的 AIM 1 中发现的变体。这两个独立但互补的 AIM 允许将数据纳入未来的决策中支持工具更适当地预测需要多少剂量的加巴喷丁才能达到所需的水平暴露，随后达到所需水平的临床反应（神经性疼痛减轻）。