A Comprehensive Monograph on Cinacalcet (DB01012): Pharmacology, Clinical Utility, and Safety Profile

Executive Summary

Cinacalcet represents a seminal achievement in the pharmacological management of mineral metabolism disorders, establishing the drug class of calcimimetics. As a first-in-class, orally administered small molecule, its primary function is as a positive allosteric modulator of the Calcium-Sensing Receptor (CaSR). This novel mechanism of action allows for the direct suppression of parathyroid hormone (PTH) secretion by increasing the sensitivity of the parathyroid gland to extracellular calcium. Consequently, cinacalcet effectively and simultaneously reduces serum levels of PTH, calcium, and phosphorus, a unique therapeutic profile that distinguishes it from other agents used in this field, such as vitamin D sterols.

The principal clinical indications for cinacalcet include the treatment of secondary hyperparathyroidism (SHPT) in adult patients with chronic kidney disease (CKD) on dialysis, the management of hypercalcemia in patients with parathyroid carcinoma, and the treatment of severe hypercalcemia in patients with primary hyperparathyroidism who are not candidates for parathyroidectomy. Its pharmacokinetic profile is characterized by rapid but variable oral absorption that is significantly enhanced by food, extensive protein binding, a long terminal half-life of 30-40 hours, and complex hepatic metabolism primarily via cytochrome P450 (CYP) enzymes CYP3A4, CYP2D6, and CYP1A2. Critically, cinacalcet is also a potent inhibitor of CYP2D6, creating a high potential for clinically significant drug-drug interactions.