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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).

项目总结尽管加巴喷丁是神经病理性疼痛患者最常用的处方药，但高疼痛减轻的可变性程度限制了疼痛的有效治疗。来自这笔赠款的工作产品将允许形成一种针对这种疾病的模型信息给药策略。这项研究将对给残疾儿科病人开药的方式。需要通过血脑屏障(BBB)运输的药物经常需要运输才能到达脑脊液(CSF)。SLC7A5基因编码一种轻链蛋白(LAT1)，形成一种异源二聚体与重链蛋白CD98hc(由SLC3A2编码)形成膜转运蛋白质称为L类氨基酸转运蛋白-1(LAT1)。此前的21项体外研究表明，该转运体是加巴喷丁跨血脑屏障转运的主要机制之一。这辆运输车是也经常被确认或推测为其他几种常用处方药的转运体由康复提供者开出的处方。确定患者血浆中加巴喷丁的量的变异性(全身暴露)和通过血脑屏障(BBB)的量(中央暴露)对于最佳确定对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儿童脑瘫患者中枢暴露(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调查中枢暴露的量。一个 AIM 1的次要部分通过执行完整的外显子组测序评估SLC7A5基因和选择的单核苷酸多态的基因分型在LAT1转运蛋白的内含子区域。目标2使用类似的方法分为两个子目标。第一个子目标评估同时使用细胞系模型也利用LAT1转运体的药物转导SLC7A5基因评价药物与常用药物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。第二个分目标是目的2通过转染LAT1转运蛋白的基因变体来确定编码区的影响此传送器的功能发生了变化。这些变异可能通过整个外显子组测序而被告知。在AIM 1中发现变种。这两个独立但互补的目标允许将数据合并到未来的决策中支持工具，以更恰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，并随后达到预期的临床反应水平(神经病理性疼痛减轻)。