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.

Chemical properties

Yellow Oil

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

The Uses of CINACALCET

macular degeneration therapy

The Uses of CINACALCET

Labeled Cinacalcet, intended for use as an internal standard for the quantification of Cinacalcet by GC- or LC-mass spectrometry.

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.

Definition

ChEBI: Cinacalcet is a secondary amino compound that is (1R)-1-(naphthalen-1-yl)ethanamine in which one of the hydrogens attached to the nitrogen is substituted by a 3-[3-(trifluoromethyl)phenyl]propyl group. It has a role as a calcimimetic and a P450 inhibitor. It is a member of naphthalenes, a secondary amino compound and a member of (trifluoromethyl)benzenes.

brand name

Sensipar (Amgen).

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.

Clinical Use

Cinacalcet hydrochloride is a second-generat ion calcimimetic approved for the treatment of secondary hyperparathyroidism in patients wi th chronic kidney disease on dialysis and for the treatment of hypercalcemia in patients with parathyroid cancer . It can be used alone, with vitamin D, and/or with a phosphate binder .

Side Effects

Common side effects of Cinacalcet are nausea, vomiting, dizziness, diarrhoea and loss of appetite.Cinacalcet can cause hypocalcaemia. Patients taking this medication need to be followed closely for common symptoms associated with hypocalcaemia, including tingling, muscle twitching, cramps, mood changes or irritability. On the ECG, there may be a prolonged QT interval. Patients with a history of congenital long QT syndrome, a family history of long QT syndrome, and other conditions predisposing them to prolonged QT intervals may be at increased risk. PTH oversupport can lead to ankylosing bone disease.

Drug interactions

Potentially hazardous interactions with other drugs
Antifungals: metabolism inhibited by ketoconazole.
Hormone antagonists: metabolism of tamoxifen to active metabolite inhibited - avoid.
Tobacco: metabolism increased by tobacco.

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.

Metabolism

Cinacalcet is rapidly and extensively metabolised by cytochrome P450 isoenzymes CYP3A4 and CYP1A2, by oxidation followed by conjugation. The major circulating metabolites are inactive, and are renally excreted, with 80% of the dose recovered in the urine, and 15% in the faeces.