Developing a prediction model for vincristine-induced peripheral neuropathy

开发长春新碱引起的周围神经病变的预测模型

• 批准号: 7832766
• 负责人: JAMIE L RENBARGER
• 金额: $ 49.28万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7832766
• 关键词: Academic Medical Centers; Acute Lymphocytic Leukemia; Address; Adult; Adverse effects; Affect; Antineoplastic Agents; Area; B-Lymphocytes; CYP3A5 gene; Cancer Patient; Candidate Disease Gene; Child; Childhood; Childhood Acute Lymphocytic Leukemia; Clinical; Clinical Research; Clinical Trials; Cytochrome P450; DNA; Data; Disease; Dose; Drug Kinetics; Enrollment; Enzymes; Evaluation; Funding; Future; Genes; Genetic; Genetic Polymorphism; Goals; Grant; Guidelines; In Vitro; Indiana; Individual; Institution; Knowledge; Lead; Malignant Neoplasms; Measurement; Metabolism; Modeling; Mus; Neuropathy; Outcome; Pathway interactions; Patients; Pediatric Oncology; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Plasma; Population; Publishing; Recommendation; Relative (related person); Research; Risk; Severities; Supported Employment; Terminology; Testing; Therapeutic; Time; Toxic effect; Treatment Efficacy; Unemployment; Validation; Variant; Vinca Alkaloids; Vincristine; Work; base; catalyst; cohort; dosage; genetic association; improved; knowledge base; neurotoxicity; prospective; public health relevance; response; tool

DESCRIPTION (provided by applicant): This application addresses broad challenge area (04) Clinical Research and Specific Challenge Topic, 04-GM-101: Personalized Drug Response and Toxicity. Vincristine is active against a wide variety of malignancies and has been shown to substantially improve outcomes. Although vincristine is among the most commonly used anticancer agents, little is known about optimal therapeutic dosing and it is widely recognized that improper dosing can lead to serious side effects or lack of efficacy. Vincristine is associated with highly variable peripheral neuropathy that often necessitates dose reductions, thereby compromising efficacy. Recently published data indicate that vincristine pharmacokinetics may be associated with long-term outcomes in children with acute lymphoblastic leukemia (ALL). Two enzymes (cytochrome P450 (CYP) 3A4 and CYP3A5) metabolize vincristine; but CYP3A5 is up to 10-times more efficient as a catalyst of vincristine metabolism in vitro. Severity of neurotoxicity may be directly related to an individual patient's vincristine exposure. It may be possible to optimize vincristine dosing based on knowledge of genetic polymorphisms in the vinca alkaloid pharmacologic pathway that may alter vincristine disposition thereby affecting the risk of neurotoxicity. The long-range goal of this research is to optimize the use of this critically important drug. The objective of this proposal is to develop a pharmacologic prediction model of vincristine induced neuropathy in pediatric ALL patients. The central hypothesis is that germline variants in candidate genes are associated with vincristine toxicity, pharmacokinetics, and efficacy. We will test this hypothesis through the following specific aims. In specific aim 1 of the proposal we will determine if there are associations between multiple common or functional variants in genes in the vinca alkaloid pathway, vincristine and metabolite concentrations, and vincristine neuropathy in a multicenter population of children with precursor B cell (preB) ALL receiving vincristine. In specific aim 2 we will utilize the data collected in the first aim to develop a pharmacologic model to characterize the associations between pharmacogenetics, pharmacokinetics, carefully characterized vincristine neuropathy and other clinical variables. The third aim is to utilize the model developed in aim 2 to develop improved dosing guidelines for use of vincristine in pediatric ALL patients to minimize neurotoxicity while optimizing efficacy. This will involve enrollment of a single cohort of 175 children with preB ALL enrolled to a multicenter prospective clinical trial. DNA and plasma pharmacokinetics will be collected and patients will be followed throughout their treatment for evidence of vincristine neurotoxicity. Vincristine neurotoxicity will be carefully evaluated using the standard NCI Common Terminology Criteria as well as more specific and sensitive neuropathy assessment tools (validated in adults) modified for use in children to provide a much more carefully characterized phenotype to facilitate the analysis of the genetic association. A second phenotyped population (140 children enrolled to a nearly completed single institution trial of pharmacogenetics of vincristine neurotoxicity) will be used as a validation cohort. We expect that this research will provide important new information regarding the association of genetic variables and vincristine toxicity and pharmacokinetics. The results will be significant because they will address an important gap in knowledge which will provide the basis for subsequent studies aimed at optimization of vincristine dosing for individual patients (utilizing the model developed as part of this proposal) in the treatment of curable pediatric diseases. The funds provided through this Challenge Grant will provide a consortium of four leading academic medical centers with a strong expertise in pediatric oncology, pharmacogenetics, clinimetrics, and clinical trials to acquire additional expertise in pharmacologic modeling. This application will support employment in the state of Indiana, which had 324,178 unemployed in April, 2009, a 10.1 % unemployment rate relative to the US unemployment rate of 8.9%. This is an 89.1% increase in unemployment in the state of Indiana since February 2008. The institutions involved in this project will work together to conduct a rigorous evaluation of pharmacogenetic predictors of vincristine neuropathy in children with preB ALL. At the end of the grant period, we expect to have the tools necessary to provide individualized vincristine dosing recommendations for children with preB ALL. In the future, we plan to build on this knowledge-base for application to other patient groups treated with vincristine to improve dosing for the nearly 40,000 cancer patients who receive this drug every year. PUBLIC HEALTH RELEVANCE: The research with vincristine that we propose is significant because it is expected to provide the knowledge base needed to determine optimal dosing of vincristine for individual pediatric patients, which has a significant potential to improve survival in the treatment of a number of curable cancers. Once the correlation between genetics and vincristine neurotoxicity fully elucidated, it will be possible to individualize vincristine dosing using genetic information to optimize therapeutic efficacy while minimizing toxicity.

描述(由申请人提供)： 这项申请涉及广泛的挑战领域(04)临床研究和特定的挑战主题，04-GM-101：个性化药物反应和毒性。 长春新碱对多种恶性肿瘤有效，并已被证明可显著改善结果。虽然长春新碱是最常用的抗癌药物之一，但人们对最佳治疗剂量知之甚少，而且人们普遍认为，不适当的剂量会导致严重的副作用或缺乏疗效。长春新碱与高度可变的周围神经病变有关，通常需要减少剂量，从而影响疗效。最近发表的数据表明，长春新碱的药代动力学可能与急性淋巴细胞白血病(ALL)儿童的长期结果有关。两种酶(细胞色素P450(CYP)3A4和细胞色素P3A5)代谢长春新碱；但在体外，细胞色素P450 3A5是长春新碱代谢的催化剂，效率高达10倍。神经毒性的严重程度可能与个别患者接触长春新碱直接相关。基于对长春新碱药理途径遗传多态的了解，有可能优化长春新碱的剂量，这可能会改变长春新碱的处置，从而影响神经毒性的风险。这项研究的长期目标是优化这种至关重要的药物的使用。本研究的目的是建立长春新碱对儿童急性淋巴细胞白血病(ALL)患者神经病变的药理学预测模型。中心假设是候选基因中的胚系变异与长春新碱的毒性、药代动力学和疗效有关。我们将通过以下具体目标来检验这一假设。在提案的具体目标1中，我们将确定长春新碱途径基因的多种常见或功能变异、长春新碱和代谢物浓度，以及在前体B细胞(PREB)均接受长春新碱治疗的多中心儿童群体中，长春新碱神经病之间是否存在关联。在具体目标2中，我们将利用第一个目标中收集的数据来开发一个药理学模型，以表征药物遗传学、药代动力学、仔细描述的长春新碱神经病和其他临床变量之间的关系。第三个目标是利用在目标2中开发的模型来开发改进的长春新碱在儿童ALL患者中使用的剂量指南，以最大限度地减少神经毒性，同时优化疗效。 这将涉及一个由175名患有Preb的儿童组成的单一队列，这些儿童都参加了一项多中心前瞻性临床试验。将收集DNA和血浆药代动力学数据，并在整个治疗过程中对患者进行跟踪，以寻找长春新碱神经毒性的证据。长春新碱的神经毒性将使用标准的NCI通用术语标准以及更具体和更敏感的神经病变评估工具(在成人中验证)进行仔细评估，以便为儿童使用而进行修改，以提供更仔细的表型特征，以便于分析遗传关联。第二个表型人群(140名儿童登记参加几乎完成的长春新碱神经毒性药物遗传学单一机构试验)将被用作验证队列。我们期望这项研究将提供关于遗传变量与长春新碱毒性和药代动力学之间关系的重要新信息。这些结果将具有重大意义，因为它们将解决知识上的一个重要差距，这将为后续旨在优化长春新碱在治疗可治愈儿科疾病中的个别患者剂量的研究(利用作为该提案的一部分开发的模型)提供基础。 通过这项挑战基金提供的资金将为一个由四个领先的学术医疗中心组成的财团提供在儿科肿瘤学、药物遗传学、临床计量学和临床试验方面的强大专业知识，以获得更多的药理学建模专业知识。这项申请将支持印第安纳州的就业，该州2009年4月有324,178人失业，失业率为10.1%，而美国的失业率为8.9%。自2008年2月以来，印第安纳州的失业率上升了89.1%。 参与该项目的机构将共同努力，对Preb ALL儿童长春新碱神经病的药物遗传学预测因素进行严格的评估。在授权期结束时，我们希望拥有必要的工具，为Preb ALL儿童提供个性化的长春新碱剂量建议。在未来，我们计划在这个知识库的基础上，将其应用于其他接受长春新碱治疗的患者群体，以改善每年接受这种药物治疗的近4万名癌症患者的剂量。 公共卫生相关性：我们建议的长春新碱研究意义重大，因为它有望提供所需的知识基础，为个别儿科患者确定长春新碱的最佳剂量，这将极有可能提高一些可治愈癌症的存活率。一旦遗传学与长春新碱神经毒性的相关性完全 阐明后，将有可能利用遗传信息来个性化长春新碱的剂量，以优化治疗效果，同时将毒性降至最低。