Repurposing rifampin to reduce elevated levels of blood and urine calcium in patients with inactivating mutations of CYP24A1

重新利用利福平可降低 CYP24A1 失活突变患者的血钙和尿钙水平升高

基本信息

批准号：
9388011
负责人：
MICHAEL ALAN LEVINE
金额：
$ 49.75万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-22 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9388011
关键词：
Adrenal Glands Adverse event Alleles Antibiotics Biological Biological Markers Blood CYP3A4 gene Calcified Calcitriol Calcium Caring Child Clinical Clinical Trials Clinical assessments Data Defect Degradation Pathway Development Diet Disease Dose Enzymes Exclusion Criteria FDA approved Failure to Thrive Feedback Food Funding Genes Genetic Genetic Polymorphism Goals Grant Health Hematuria Hereditary Disease Hypercalcemia Hypersensitivity Infant Infantile hypercalcemia Intestinal Absorption Intestines Kidney Kidney Calculi Kidney Failure Knowledge Laboratories Life Liver Liver Function Tests Medical Metabolic Metabolism Mission Mixed Function Oxygenases Monitor Monte Carlo Method Mutation Nephrocalcinosis Nephrolithiasis Online Mendelian Inheritance In Man Oral Outcome Outcomes Research Pathway interactions Patients Pharmaceutical Preparations Phase Plasma Probability Production Protocols documentation Recurrence Regimen Request for Proposals Research Research Design Research Project Grants Resources Rifampin Risk Role Safety Sample Size Sampling Scheme Serum Study Subject Sun Exposure Testing United States National Institutes of Health Urine Vitamin D Vitamin D supplementation base calcification calcium absorption clinical investigation design design and construction effective therapy hypercalciuria improved infancy innovation models and simulation novel novel strategies novel therapeutic intervention open label predicting response primary outcome response secondary outcome standard care standard of care success ultraviolet irradiation urinary

项目摘要

Project Summary/Abstract This proposal requests funding for a phase IIa clinical trial of rifampin, an FDA-approved antibiotic, for safety and efficacy as a treatment for idiopathic infantile hypercalcemia (IIH). IIH is an uncommon metabolic condition characterized by elevated plasma levels of the activated form of vitamin D, calcitriol, and consequently increased intestinal absorption of calcium that leads to hypercalcemia and hypercalciuria. Although IIH typically presents in infancy, patients manifest a life-long defect in vitamin D metabolism that results in hematuria, renal calcification, and renal insufficiency. Biallelic inactivating mutations of CYP24A1, the gene encoding the 24- hydroxylase enzyme that represents the principal pathway for inactivation of vitamin D metabolites, cause the most common and severe form of IIH. The loss of this degradative pathway allows plasma levels of calcitriol to rise excessively and overcomes negative feedback mechanisms that should downregulate production of calcitriol. There is at present no specific long-term treatment for patients with CYP24A1 mutations and IIH, and conventional care consists of minimizing sunlight exposure, a low calcium diet, and avoidance of vitamin D-rich foods and vitamin D supplements, but this approach does not reduce the risk of renal calcification and renal insufficiency. Thus, there is a significant unmet medical need for safe and effective treatments for this disorder. We have compelling data supporting a novel therapeutic approach that repurposes rifampin to induce expression of CYP3A4, an enzyme that is expressed in the liver and intestine and when over expressed provides an alternative pathway for inactivation of vitamin D metabolites. The long-term goal of this project is to use knowledge of enzymatic pathways that regulate vitamin D metabolism to develop novel strategies for medical treatment of patients with IIH and other forms of hypercalciuria and nephrolithiasis that are associated with elevated plasma levels of calcitriol. The objective in this application is to determine the optimal safe and effective dose of rifampin that normalizes serum and urine levels of calcium and reduces intestinal absorption of calcium (primary outcomes). Our complementary goals are to evaluate the extent to which these primary outcomes are related to plasma levels of rifampin, induction of CYP3A4, polymorphisms in the CYP3A4 gene, and changes in plasma levels of vitamin D metabolites. Our central hypothesis is that induction of CYP3A4 by rifampin will reduce levels of calcitriol, in the plasma and/or intestine, and thereby decrease intestinal absorption of calcium. We expect that overall benefits will be strongly associated with the extent of CYP3A4 induction. Our secondary aim is to use our results to drive a clinical trials simulator that will inform our development of a protocol for a larger, Phase IIb pivotal trial of rifampin for IIH. We have access to the necessary study subjects and the expertise and resources to pursue these studies. Our approach is innovative because it proposes to repurpose a well-characterized and safe medication to a new role as a primary therapy for a disorder that currently lacks an effective treatment.

项目摘要/摘要该提案要求为安全性的Rifampin（Rifampin）进行IIA期临床试验的资金。和功效作为特发性婴儿高钙血症（IIH）的治疗方法。 IIH是一种罕见的代谢状况以维生素D，钙三醇激活形式的血浆水平升高，因此特征钙的肠道吸收增加，导致高钙血症和高钙尿症。尽管IIH通常是在婴儿期的出现，患者表现出长期的维生素D代谢缺陷，导致血尿，肾脏钙化和肾功能不全。 CYP24A1的双重灭活突变，编码24-的基因代表灭活维生素D代谢物的主要途径的羟化酶酶导致 IIH的最常见和严重形式。这种降解途径的损失使血浆钙化水平达到过度上升，克服了应下调产生的负面反馈机制钙三醇。目前尚无针对CYP24A1突变和IIH患者的特定长期治疗，以及常规护理包括最大程度地减少阳光的暴露，低钙饮食以及避免维生素D丰富食品和维生素D补充剂，但这种方法并不能降低肾脏钙化和肾脏的风险不足。因此，对这种疾病的安全有效治疗有很大的未满足医疗需求。我们拥有令人信服的数据，支持一种新型的治疗方法，可重新利用利福平诱导 CYP3A4的表达，CYP3A4，一种在肝脏和肠中表达的酶，当过度表达时为灭活维生素D代谢物提供了替代途径。该项目的长期目标是利用调节维生素D代谢的酶促途径的知识来制定新的策略 IIH和其他形式的高钙尿和肾石岩症患者的医学治疗血浆钙化水平升高。本应用程序的目的是确定最佳安全和利福平的有效剂量使钙的血清和尿液水平归一化并降低肠道吸收钙（主要结果）。我们的互补目标是评估这些主要的程度结局与利福平血浆水平，CYP3A4的诱导，CYP3A4基因中的多态性有关，维生素D代谢物的血浆水平的变化。我们的核心假设是通过利福平将在血浆和/或肠中降低钙三醇的水平，从而降低肠道钙的吸收。我们预计总体收益将与CYP3A4的范围密切相关就职。我们的次要目的是利用我们的结果来推动临床试验模拟器，以告知我们开发利福平较大的IIB相关试验IIH的方案。我们可以访问必要的研究对象以及追求这些研究的专业知识和资源。我们的方法是创新的，因为它提议将良好特征和安全的药物重新利用为新作用，作为疾病的主要疗法目前缺乏有效的治疗方法。