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）： 该申请涉及广泛的挑战领域（04）临床研究和特定挑战主题，04-gm-101：个性化药物反应和毒性。 长春新碱对各种恶性肿瘤具有活跃性，并且已显示可大大改善预后。尽管长春新碱是最常用的抗癌药之一，但对最佳治疗剂量的了解鲜为人知，并且广泛认识到，不当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相关，通常需要降低剂量，从而损害疗效。最近发布的数据表明，长春蛋白药代动力学可能与急性淋巴细胞白血病儿童的长期结局有关（ALL）。两种酶（细胞色素P450（CYP）3A4和CYP3A5）代谢长春新碱；但是CYP3A5在体外的催化剂催化剂中最多可高效10倍。神经毒性的严重程度可能与单个患者的长春新碱暴露直接相关。可能会根据对VINCA生物碱药理学途径中遗传多态性的了解来优化vincristine剂量，从而可能改变长春新碱的处置，从而影响神经毒性的风险。这项研究的远程目标是优化这种至关重要的药物的使用。该提案的目的是开发一种在所有患者的小儿诱发神经病的药理学预测模型。中心假设是候选基因的种系变异与长春新碱的毒性，药代动力学和功效有关。我们将通过以下特定目标检验这一假设。在该提案的特定目的1中，我们将确定在VINCA生物碱途径，vincristine和nemapolite浓度中是否存在多种常见或功能变异之间的关联，而在具有前体B细胞（PERB）的多中心群体中，所有接受vincristine的儿童的多中心人群中是否存在关联。在特定的目标2中，我们将利用第一个目的中收集的数据来开发药物模型来表征药物遗传学，药代动力学，精心表征vincristine神经病和其他临床变量之间的关联。第三个目的是利用AIM 2中开发的模型来制定用于在所有患者的小儿使用长春新碱的剂量指南，以最大程度地降低神经毒性，同时优化效果。 这将涉及入学的175名PERB儿童的单一队列，均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，并在整个治疗过程中遵循患者，以证明长春新碱神经毒性的证据。将使用标准的NCI常见术语标准以及更具体和敏感的神经病评估工具（在成人验证）中仔细评估vincristine神经毒性。第二次表型人口（140名儿童参加了Vincristine神经毒性的几乎完成的单一机构试验）将用作验证队列。我们预计这项研究将提供有关遗传变量和长春新碱毒性和药代动力学的关联的重要新信息。结果将是重要的，因为它们将解决知识的重要差距，这将为随后的研究提供旨在优化单个患者长春新碱给药的基础（利用该模型作为本提案的一部分），以治疗可治愈的儿科疾病。 通过这项挑战赠款提供的资金将为四个领先的学术医学中心提供一个财团，在儿科肿瘤学，药物遗传学，临床和临床试验方面具有强大的专业知识，以获得药理学建模方面的更多专业知识。该申请将支持印第安纳州的就业，2009年4月失业324,178，相对于美国失业率为8.9％的失业率为10.1％。自2008年2月以来，印第安纳州的失业率增加了89.1％。 该项目所涉及的机构将共同进行对PERB儿童的vincristine神经病的药物遗传学预测因子进行严格的评估。在赠款期结束时，我们希望拥有必要的工具，为所有Preb的儿童提供个性化的Vincristine剂量建议。将来，我们计划以这种知识库为基础，以应用于其他接受vincristine治疗的患者群体，以改善每年接受该药物的近40,000名癌症患者的剂量。 公共卫生相关性：我们提出的vincristine的研究很重要，因为它有望提供确定个体儿科患者的最佳剂量剂量所需的知识库，这具有提高许多可治愈癌症的生存的巨大潜力。一旦遗传学与长春蛋白神经毒性之间的相关性完全 阐明，可以使用遗传信息来个性化vincristine剂量，以优化治疗功效，同时最大程度地减少毒性。