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

• 批准号: 9980393
• 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
• 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/9980393
• 关键词: Adrenal Glands; Adverse event; Alleles; Antibiotics; Biological; Biological Markers; Blood; CYP3A4 gene; 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 Diseases; Genetic Polymorphism; Goals; Grant; Health; Hematuria; 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; pharmacokinetics and pharmacodynamics; predicting response; primary outcome; response; secondary outcome; standard care; standard of care; success; ultraviolet irradiation; urinary

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 该提案要求为利福平的IIa期临床试验提供资金，利福平是fda批准的一种抗生素，用于安全性。 以及对特发性婴儿高钙血症(IIH)的治疗效果。IIH是一种罕见的代谢性疾病 以血浆中活性形式的维生素D、骨化三醇水平升高为特征的，因此 肠道对钙的吸收增加，导致高钙血症和高钙尿。尽管IIH通常 在婴儿期，患者表现出终身的维生素D代谢缺陷，导致血尿、肾脏 钙化和肾功能不全。CYP24A1基因的双等位基因失活突变 代表维生素D代谢物失活的主要途径的羟基酶，导致 最常见和最严重的IIH形式。这种降解途径的丧失使血浆骨化三醇水平 过度上涨，克服应下调产量的负反馈机制 骨化三醇。目前还没有针对CYP24A1突变和IIH患者的特定长期治疗方法，以及 传统护理包括尽量减少阳光曝晒、低钙饮食和避免富含维生素D 食物和维生素D补充剂，但这种方法并不能降低肾脏钙化和肾脏的风险 不够用。因此，对于这种疾病的安全和有效的治疗，存在着巨大的未得到满足的医疗需求。 我们有令人信服的数据支持一种新的治疗方法，即改变利福平诱导 肝脏和肠道中表达的一种酶--细胞色素P3A4的表达 为维生素D代谢物的失活提供了另一种途径。这个项目的长期目标是 利用调节维生素D代谢的酶途径的知识来开发新的策略 IIH及与之相关的其他形式的高钙尿和肾结石的内科治疗 血浆骨化三醇水平升高。此应用程序的目标是确定最优的安全和 利福平的有效剂量，可使血清和尿钙水平正常化，并减少肠道吸收 钙的含量(主要结果)。我们的互补目标是评估这些主要因素在多大程度上 预后与血浆利福平水平、细胞色素P3A4的诱导、细胞色素P3A4基因的多态、 以及血浆维生素D代谢物水平的变化。我们的中心假设是通过诱导细胞色素P3A4 利福平将降低血浆和/或肠道中的骨化三醇水平，从而减少肠道 钙的吸收。我们预计，总体收益将与CYP3A4的程度密切相关 归纳法。我们的第二个目标是利用我们的结果来驱动一个临床试验模拟器，它将为我们的 制定一项用于IIH的更大规模、IIb期利福平关键试验的方案。我们有权获得必要的 研究对象以及从事这些研究的专业知识和资源。我们的方法是创新的，因为它 建议将一种具有良好特性和安全的药物重新定位为一种新的角色，作为一种疾病的主要治疗方法 目前缺乏有效的治疗方法。