The Antibiotic Rifampin to Reduce High Levels of Blood and Urine Calcium in IIH

The Hospital for Sick Children

Status and phase

Unknown

Phase 1

Conditions

Idiopathic Infantile Hypercalcemia - Mild Form

Treatments

Drug: Rifampin 150 mg, 300 mg capsules and 25 mg/mL oral suspension

Study type

Interventional

Funder types

Other

Identifiers

NCT03384121

1000057141

Details and patient eligibility

About

Idiopathic infantile hypercalcemia(IIH) is a rare,genetic disorder of mineral metabolism. Biallelic loss of functions 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.Investigators have preliminary data supporting a novel therapeutic approach to suggest rifampin as an investigational drug to induce over-expression of CYP3A4, an important enzyme that provides an alternate catabolic pathway for inactivation of vitamin D metabolites. In this study, investigators will recruit 5 patients with biallelic inactivating mutations of CYP24A1. Participants will be followed prospectively for a total 6-11 months. This will include 2 months of observation, 2 months of receiving the starting dose of rifampin, followed by 2 month washout phase. Efficacy of the starting dose of rifampin will be determined prior to proceeding only in non responders to the escalation dose of rifampin 10mg/kg/day.

Full description

Idiopathic infantile hypercalcemia(IIH) is a rare,genetic disorder of mineral metabolism characterized by severe hypercalcemia and/or hypercalciuria, suppressed serum levels of parathyroid hormone (PTH), elevated levels of the active vitamin D metabolite, 1,25(OH)2D, and nephrocalcinosis. Biallelic loss of functions 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.

Investigators have preliminary data supporting a novel therapeutic approach to suggest rifampin as an investigational drug to induce over-expression of CYP3A4, an important P450 microsomal enzyme that is expressed in the liver and intestine. When CYP3A4 is induced, the increased enzyme activity provides an alternative catabolic pathway for inactivation of vitamin D metabolites. The purpose of this study is to obtain results and support for an open label, escalating dose study to assess the effect, safety, and tolerability of once daily oral rifampin for two months in participants with IIH due to inactivating mutations in CYP24A1.

In this study, Investigators will recruit 5 patients with biallelic inactivating mutations of CYP24A1. Participants will be followed prospectively for a total 6-11 months. This will include 2 months of observation, 2 months of receiving the starting dose of rifampin, followed by 2 month washout phase. Efficacy of the starting dose of rifampin will be determined prior to proceeding only in non responders to the escalation dose of rifampin 10mg/kg/day. In addition to determining if this treatment is efficacious in reducing elevated serum and urinary calcium in patients, it will be determined if there is a dose effect of rifampin. As well, detailed measurements of vitamin D metabolites will determine if rifampin reduces hypercalcemia through increased CYP3A4 activity.

Enrollment

5 estimated patients

Sex

All

Ages

6 months to 17 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

all patients between 6 months- 17 years of age with the clinical phenotype of idiopathic infantile hypercalcemia
Biochemical evidence of this disorder: Serum calcium>upper limit of the reference age for range; high, 1,25 (OH)D; reduced PTH, reduced 24,25(OH)2D, and suppresses 24,1,25 (OH)2D, normal serum creatinine, AST, and ALT with or without
biallelic inactivating mutations of CYP24A1
mutations in newly published genes which are shown during the course of the study to cause an inappropriate increase in 1,25 (OH)2D

Exclusion criteria

Allergy to rifampin or related medications
Pregnancy or breastfeeding
Significant cardiac, hepatic, or endocrine comorbidities
Taking any medications/foods known to interact with CYP3A4 or 1,25 (OH)D
Parents or guardians or subjects who in the opinion of the Investigator may be non compliant with study schedules or procedures
Other comorbidities considered unsuitable by the investigator, including TB