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）： 本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。 阿曲斯汀对多种恶性肿瘤具有活性，并已被证明可显著改善结局。虽然长春新碱是最常用的抗癌药物之一，但对最佳治疗剂量知之甚少，并且广泛认为剂量不当可导致严重副作用或缺乏疗效。阿曲斯汀与高度可变的周围神经病变相关，这通常需要减少剂量，从而影响疗效。最近发表的数据表明，长春新碱药代动力学可能与急性淋巴细胞白血病（ALL）儿童的长期结局相关。两种酶（细胞色素P450（CYP）3A 4和CYP 3A 5）代谢长春新碱;但CYP 3A 5作为长春新碱体外代谢催化剂的效率高达10倍。神经毒性的严重程度可能与个体患者的长春新碱暴露直接相关。基于对可能改变长春新碱处置从而影响神经毒性风险的长春花生物碱药理学途径中遗传多态性的了解，可能优化长春新碱给药。这项研究的长期目标是优化这种至关重要的药物的使用。本提案的目的是开发儿童ALL患者中长春新碱诱导神经病变的药理学预测模型。中心假设是候选基因的生殖系变异与长春新碱毒性、药代动力学和疗效相关。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，我们将确定在接受长春新碱治疗的前体B细胞（前B）ALL儿童多中心人群中，长春花生物碱途径基因中的多种常见或功能性变异体、长春新碱和代谢产物浓度以及长春新碱神经病变之间是否存在关联。在具体目标2中，我们将利用第一个目标中收集的数据开发药理学模型，以表征药物遗传学、药代动力学、仔细表征的长春新碱神经病变和其他临床变量之间的相关性。第三个目的是利用目的2中开发的模型，制定长春新碱在儿童ALL患者中使用的改进剂量指南，以最大限度地减少神经毒性，同时优化疗效。 这将涉及一项多中心前瞻性临床试验中入组的175名前B ALL儿童的单个队列。将采集DNA和血浆药代动力学数据，并在整个治疗期间对患者进行随访，以获得长春新碱神经毒性的证据。将使用标准的NCI通用术语标准以及更特异和灵敏的神经病变评估工具（在成人中验证）仔细评价阿贝斯汀神经毒性，这些工具经修改用于儿童，以提供更仔细表征的表型，以便于分析遗传相关性。第二个表型人群（140名儿童入组一项接近完成的长春新碱神经毒性药物遗传学单机构试验）将用作验证队列。我们希望这项研究将提供有关遗传变量与长春新碱毒性和药代动力学相关性的重要新信息。这些结果将具有重要意义，因为它们将解决一个重要的知识空白，这将为后续研究提供基础，旨在优化个体患者（利用作为本提案一部分开发的模型）治疗可治愈儿科疾病的长春新碱剂量。 通过这项挑战赠款提供的资金将提供一个由四个领先的学术医疗中心组成的联盟，这些中心在儿科肿瘤学，药物遗传学，临床计量学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额外专业知识。此应用程序将支持印第安纳州的就业，该州在2009年4月有324，178人失业，相对于美国8. 9%的失业率，失业率为10. 1%。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儿童中长春新碱神经病变的药物遗传学预测因子进行严格评价。在资助期结束时，我们希望有必要的工具为preB ALL儿童提供个性化的长春新碱给药建议。未来，我们计划在此基础上应用于其他接受长春新碱治疗的患者群体，以改善每年接受该药物治疗的近40，000名癌症患者的剂量。 公共卫生相关性：我们提出的长春新碱研究具有重要意义，因为它有望为确定个体儿科患者的长春新碱最佳剂量提供所需的知识基础，这对改善许多可治愈癌症治疗的生存率具有重要潜力。一旦遗传学与长春新碱神经毒性之间的相关性充分 阐明，将有可能使用遗传信息个体化长春新碱给药，以优化疗效，同时最大限度地减少毒性。