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

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $701,043

## Abstract

Project Summary/Abstract
This proposal requests funding for continuation and extension of a phase IIa clinical trial of rifampin, an FDA-
approved antibiotic, for safety and efficacy as a treatment for idiopathic infantile hypercalcemia (IIH) due to
mutations in the gene encoding CYP24A1 gene. 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 and increased bone resorption that together cause hypercalcemia and hypercalciuria.
Although IIH typically presents in infancy, patients manifest a life-long defect in vitamin D metabolism that results
in hypercalciuria, nephrolithiasis, and renal insufficiency. CYP24A1 encodes the 24-hydroxylase enzyme that
represents the principal pathway for inactivation of vitamin D metabolites, and biallelic mutations cause the most
common and severe form of IIH. Loss of this pathway allows plasma levels of calcitriol to rise excessively and
overcomes feedback mechanisms that should downregulate production of calcitriol. Patients who carry only one
defective CYP24A1 allele have a less severe phenotype. There is at present no specific long-term treatment for
patients with CYP24A1 mutations and conventional care consists of minimizing sunlight exposure, a low calcium
diet, and avoidance of vitamin D-rich foods and vitamin D supplements. This approach does not reduce the risk
of renal calcification and renal insufficiency, however, and may lead to low bone density. Thus, there is a
significant unmet medical need for safe and effective treatments for this disorder. We have compelling data
supporting a therapeutic approach in which the antibiotic rifampin is repurposed to induce expression of CYP3A4,
an enzyme that is expressed in the liver and intestine, to provide an alternative pathway for inactivation of vitamin
D metabolites. The long-term goal of this project is 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 two 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 other genes that influence
mineral metabolism, and changes in plasma levels of vitamin D metabolites and to determine the effect of
CYP24A1 mutations on bone health. Our central hypothesis is that induction of CYP3A4 by rifampin will reduce
levels of calcitriol and thereby decrease intestinal absorption of calcium and we expect that benefits will be related
to the extent of CYP3A4 induction. We have access to the necessary study subjects and the expe...

## Key facts

- **NIH application ID:** 10756989
- **Project number:** 5R01DK112955-07
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Michael A. Levine
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $701,043
- **Award type:** 5
- **Project period:** 2022-12-23 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10756989

## Citation

> US National Institutes of Health, RePORTER application 10756989, Repurposing rifampin to reduce elevated levels of blood and urine calcium in patients with inactivating mutations of CYP24A1 (5R01DK112955-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10756989. Licensed CC0.

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