Cinacalcet

(R )-N- [1 - ( 1-naphthyl ) ethyl] -3 - [3 - ( trifluoromethyl) phenyl] propan- 1-amine

• C22H22F3N ( cinacalcet )
• C22H22F3N · HCl ( cinacalcet · hydrochloride)

• 226256-56-0 ( cinacalcet )
• 364782-34-3 ( cinacalcet · hydrochloride)

H05BX01

• 357.41 g · mol -1 ( cinacalcet )
• 393.87 g · mol -1 ( · cinacalcet hydrochloride)

Template: Infobox chemical / molecular formula search available

Cinacalcet is a drug in the treatment of primary and secondary hyperparathyroidism - a disease of the adrenal gland.

Mechanism of Action

Cinacalcet is an allosteric modulator of the calcium sensing receptor and leads to a conformational change of its tertiary structure. This causes an increase of the sensitivity of the receptor to calcium, and in a reduced release of the hormone, parathyroid hormone, bone metabolism. The effect of the calcium- sensing receptor, cinacalcet on the parathyroid is about 100 times stronger than the effect on calcium- sensitive receptors of other tissues, such as the C cells of the thyroid gland. This may explain why even small doses of cinacalcet inhibit the production of parathyroid hormone in the parathyroid gland without causing serious side effects in other organs and tissues that also express calcium- sensitive receptors.

Stereoisomerism

Cinacalcet contains a stereogenic center. As a drug, the pure ( R)-enantiomer is used. The fluorine-containing, chiral organic chemical compound is selected from the group of the naphthalene derivatives.

Admission

Cinacalcet is an EU-wide since 2004 under the trade name Mimpara ® on the market, the manufacturer is Amgen. In the U.S., the trade name Sensipar ® is.

The approval extends to the treatment

• Of secondary hyperparathyroidism in patients with renal failure requiring dialysis, in conjunction with phosphate binders, and vitamin D
• Of hypercalcemia in the parathyroid carcinoma and
• Of hypercalcemia in primary hyperparathyroidism, in which surgical removal of the parathyroid glands would be appropriate in a particular case is not possible, however.

Animal data

In animals with chronic renal failure cinacalcet leads

• A drop in the synthesis and release of parathyroid hormone in the parathyroid gland,
• An up-regulation of the calcium sensing receptor and vitamin D receptor
• To decreased proliferation of the parathyroid cells,
• To a reduced progression of parathyroid enlargement (hyperplasia ),
• To an increased programmed cell death ( apoptosis) of parathyroid cells
• To a reduced progression induced by parathyroid hormone level changes to the bone ( osteitis fibrosa ) and
• In reduced progression of calcium deposits in the arteries.

Studies in humans

In patients with primary hyperparathyroidism or chronic hemodialysis patients taking cinacalcet leads within 2-4 hours to give a rapid decrease of parathyroid hormone. In dialysis patients, but not in patients with primary hyperparathyroidism, occurs within 4-8 hours a decrease in serum calcium.

The long-term use of Cinacalcet in primary hyperparathyroidism leads to a slow decrease of the previously elevated calcium levels and an increase in phosphate levels, parathyroid hormone levels change only slightly.

In dialysis patients, the long-term administration of cinacalcet to an increasing decline of parathyroid hormone, calcium and phosphate levels leads. The secondary hyperparathyroidism can be kept for years under control.

In patients with chronic kidney disease stage 3 and 4 cinacalcet lowers parathyroid hormone levels. Serum calcium is reduced, the serum phosphate increases. High levels of urinary calcium excretion, which decreases phosphate excretion increases.

After a kidney transplant hyperparathyroidism persisting hypercalcemia and hypophosphatemia leads due to increased excretion of phosphate by the kidney. Cinacalcet results in this situation to a normalization of phosphate excretion and serum phosphate.

Currently, however, completed studies in humans are limited to the effect of cinacalcet on so-called surrogate parameters, such as parathyroid hormone, calcium and phosphate.

Studies that examine the effects of treatment with cinacalcet on clinically relevant endpoints are currently being carried out first. One study examined in dialysis patients the effect of cinacalcet on the calcification of the aortic valve. A second study examined the effects of a treatment of dialysis patients with cinacalcet on mortality and cardiovascular endpoints such as heart attack, stroke, etc. So far it is not clear whether the use of cinacalcet in patients with chronic kidney disease who do not yet need dialysis treatment, is useful.

Side effects

Most common side effects of cinacalcet are nausea and vomiting. A slow increase in the dose may help to reduce the side effects.

A study on the safety of use in pediatric patients has been canceled as a precaution in February 2013 after the death of a 14- year-old patient, even if it was not clear whether the drug has led to the death. Possible side effects could be a hypocalcemia with subsequent seizures up to laryngospasm or cardiac arrhythmias by prolonging the QT interval, which is why the check for the occurrence of hypocalcaemia is particularly important.