Rifampin in CYP24A1-related Hypercalcemia and Hypercalciuria

Idiopathic infantile hypercalcemia (IIH; omim 143880) is a genetic disorder of mineral
metabolism characterized by severe hypercalcemia and/or hypercalciuria, suppressed serum
levels of parathyroid hormone (PTH) and elevated levels of the active vitamin D metabolite,
1,25(OH)2D. 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.

Investigators have preliminary data supporting a novel therapeutic approach to repurpose
rifampin as an agent to induce over-expression of CYP3A4, an 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 support for an open label, escalating dose study to assess the effect,
safety, and tolerability of once daily oral rifampin in participants with IIH due to
inactivating mutations in CYP24A1.

In this study, Investigators will recruit 18 patients with biallelic inactivating mutations
of CYP24A1. Participants will be observed for 8-weeks before a 16-week treatment phase of
rifampin and 8 further weeks of observation. In addition to following the effect of treatment
on calcium homeostasis, Investigators will also study the pharmacokinetics of rifampin in
this condition and the effect on intestinal calcium absorption.

Inclusion Criteria:

- Males or females age 6 months to 50 years.

- Biallelic mutations of CYP24A1

- Serum and/or urinary calcium above the normal reference range for age

- Serum PTH concentration <20 pg/ml

- Elevated or normal serum concentration of 1,25-dihydroxyvitamin D3.

Exclusion Criteria:

- Parents/guardians or subjects who, in the opinion of the Investigator, may be
non-compliant with study schedules or procedures.

- Allergy to rifampin or related medications

- Current therapies with medications or foods that are considered by the research team
to potentially affect mineral metabolism, alter clearance of rifampin, or inhibit
CYP3A4.

- Pregnancy or breastfeeding

- Laboratory abnormalities that indicate clinically significant hepatic, or renal
disease:

AST/SGOT > 2.0 times the upper limit of normal ALT/SGPT > 2.0 times the upper limit of
normal Total bilirubin > 2.0 times the upper limit of normal Creatinine > 2.0 times the
upper limit of normal