# 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 · 2021 · $452,039

## Abstract

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...

## Key facts

- **NIH application ID:** 10170333
- **Project number:** 5R01DK112955-05
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Michael A. Levine
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $452,039
- **Award type:** 5
- **Project period:** 2017-08-22 → 2022-12-22

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170333

## Citation

> US National Institutes of Health, RePORTER application 10170333, Repurposing rifampin to reduce elevated levels of blood and urine calcium in patients with inactivating mutations of CYP24A1 (5R01DK112955-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10170333. Licensed CC0.

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