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 and CYP3A5, enzymes that are expressed in the liver and intestine. When these enzymes are 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 60 patients with at least one inactivating mutation 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 65 years.
• at least one 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 that have significant drug-drug interactions with rifampin, defined as a medication considered to interact with CYP3A4 or CYP3A5 and either induce or inhibit expression or function of these P450 enzymes. By "drug-drug" interactions we are looking for medications that will affect metabolism or action of rifampin as exclusionary, not medications that will be affected by rifampin.
• Pregnancy or breastfeeding
• Laboratory abnormalities that indicate clinically significant hepatic, or renal disease:
• Aspartate Aminotransferase (AST/SGOT) > 2.0 times the upper limit of normal Alanine aminotransferase (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