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

• 批准号: 10380258
• 负责人: Matthew McLaughlin
• 金额: $ 15.12万
• 依托单位: CHILDREN'S MERCY HOSP (KANSAS CITY, MO)
• 依托单位国家: 美国
• 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/10380258
• 关键词: Address; Adopted; Adverse event; Age; Amino Acid Transporter; Appearance; Baclofen; Blood; Blood - brain barrier anatomy; Calcium Channel; 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; base; care seeking; cohort; design; disability; effective therapy; exome sequencing; functional disability; functional outcomes; gabapentin; gene interaction; genetic variant; improved; kidney cell; 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; uptake; voltage

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).

项目摘要 尽管加巴喷丁是针对神经性疼痛的患者最常见的药物，但很高 疼痛限制减少的可变性水平可有效治疗疼痛。这笔赠款的工作产品将允许 该疾病的模型信息剂量策略的形成。这项研究将对 为残疾儿科患者开处方药的方式。 需要在血脑屏障（BBB）上运输的药物经常需要运输才能到达 脑脊液（CSF）。基因SLC7A5编码形成一个的轻链蛋白（LAT1） 与重链蛋白CD98HC（由SLC3A2编码）的杂化二聚体创建膜传输 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BBB的主要机制之一。这个转运蛋白是 还有其他几种常规药物的确认或理论转运蛋白 由康复提供者处方。 确定患者在血浆中的加巴喷丁的变异性（全身暴露）和 横穿血脑屏障（BBB）（中央暴露）的数量对于最佳确定 每个孩子最合适的剂量（AIM1）。我的研究策略的总体目标是确定 影响小儿CP患者中央暴露（脑脊液）变异性的因素。目标1 通过确定穿越BBB的Gabapentin的量来研究中央暴露量。一个 AIM 1的次要部分通过执行整体 评估选定单核苷酸多态性的SLC7A5基因和基因分型的外显子组测序 在LAT1转运蛋白的内含子区域。 AIM 2使用类似的方法将两个子iam分为两个子iam。第一个子aim评估了 同时使用的药物也使用LAT1转运蛋白使用细胞系模型 用SLC7A5基因转染，以评估潜在的药物相互作用 康复医学中的药物，特别是左旋多巴，巴氯芬和前伽巴林。第二个子 AIM 2涉及转染LAT1转运蛋白的遗传变异，以确定编码区域的影响 更改该转运蛋白的功能。这些变体可以通过整个外观测序来告知 AIM 1中发现的变体。 这两种独立但互补的目标都允许将未来决定纳入的数据 支持工具以更适当地预测需要什么剂量的加巴喷丁才能达到所需的水平 暴露，随后是所需的临床反应水平（神经性疼痛减轻）。