CINACALCET

Absorption

Rapidly absorbed following oral administration.

Toxicity

Doses titrated up to 300 mg once daily have been safely administered to patients on dialysis. Overdosage of cinacalcet may lead to hypocalcemia.

Description

Cinacalcet is the first type II calcimimet ic agent approved that improves CaSR sensi Tivity to calcium . When calcium is bound to the CaSR, phospholipase C is act ivated, and the secretion of PTH is inhibited. In the presence of cinacalcet , not only is a drop in PTH levels observed but also a decrease in serum calcium and phosphorous levels.

The Uses of CINACALCET

Cinacalcet is the first calcimimetic drug approved by the United States Food and Drug Administration for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease

Indications

For the treatment of secondary hyperparathyroidism in patients with Chronic Kidney Disease who are on hemodialysis or peritoneal dialysis. Also for the treatment of hypercalcemia in patients with parathyroid carcinoma.

Background

Cinacalcet is a calcimimetic sold by Amgen under the trade name Sensipar? in North America and Australia and as Mimpara? in Europe. It is used to treat hyperparathyroidism due to parathyroid tumours or renal failure.

Pharmacokinetics

Cinacalcet is a drug that acts as a calcimimetic (i.e. it mimics the action of calcium on tissues). Secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) is a progressive disease, associated with increases in parathyroid hormone (PTH) levels and derangements in calcium and phosphorus metabolism. Increased PTH stimulates osteoclastic activity resulting in cortical bone resorption and marrow fibrosis. The goals of treatment of secondary hyperparathyroidism are to lower levels of PTH, calcium, and phosphorus in the blood, in order to prevent progressive bone disease and the systemic consequences of disordered mineral metabolism. In CKD patients on dialysis with uncontrolled secondary HPT, reductions in PTH are associated with a favorable impact on bone-specific alkaline phosphatase (BALP), bone turnover and bone fibrosis. Cinacalcet reduces calcium levels by increasing the sensitivity of the calcium sensing receptor to extracellular calcium.

Metabolism

Metabolism is hepatic by multiple enzymes, primarily CYP3A4, CYP2D6, and CYP1A2. After administration of a 75 mg radiolabeled dose to healthy volunteers, cinacalcet was rapidly and extensively metabolized via: 1) oxidative N-dealkylation to hydrocinnamic acid and hydroxy-hydrocinnamic acid, which are further metabolized via ?-oxidation and glycine conjugation; the oxidative N-dealkylation process also generates metabolites that contain the naphthalene ring; and 2) oxidation of the naphthalene ring on the parent drug to form dihydrodiols, which are further conjugated with glucuronic acid.