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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：
10170333
负责人：
MICHAEL ALAN LEVINE
金额：
$ 45.2万
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 2022-12-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10170333
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

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.

项目总结/文摘