Cinacalcet
| Structural formula | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
||||||||||||||||
| General | ||||||||||||||||
| Non-proprietary name | Cinacalcet | |||||||||||||||
| other names |
( R ) - N - [1- (1-Naphthyl) ethyl] -3- [3- (trifluoromethyl) phenyl] propan-1-amine |
|||||||||||||||
| Molecular formula |
|
|||||||||||||||
| External identifiers / databases | ||||||||||||||||
|
||||||||||||||||
| Drug information | ||||||||||||||||
| ATC code | ||||||||||||||||
| properties | ||||||||||||||||
| Molar mass | ||||||||||||||||
| safety instructions | ||||||||||||||||
|
||||||||||||||||
| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | ||||||||||||||||
Cinacalcet (trade name in the EU Mimpara ® ; manufacturer Amgen ) is a drug for the treatment of primary and secondary hyperparathyroidism - a disease of the parathyroid gland .
Mechanism of action
Cinacalcet is an allosteric modulator of the calcium-sensitive receptor and leads to a conformational change in its tertiary structure. This causes an increase in the sensitivity of the receptor for calcium and a reduced release of the bone metabolism hormone parathyroid hormone . The effect of cinacalcet on the calcium-sensitive receptor of the parathyroid gland is about 100 times stronger than the effect on calcium-sensitive receptors in other tissues, e.g. B. 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. The pure ( R ) -enantiomer is used as the medicinal substance . The fluorine-containing , chiral organic chemical compound comes from the group of naphthalene derivatives.
Admission
Cinacalcet has been on the EU- wide market since 2004 under the trade name Mimpara ® , the manufacturer is Amgen . In the USA the trade name is Sensipar ® .
The approval extends to the treatment
- secondary hyperparathyroidism in patients with kidney failure requiring dialysis in connection with phosphate binders and vitamin D , since September 2017 also approved for children aged three and over,
- of hypercalcemia in parathyroid carcinoma and
- hypercalcemia in primary hyperparathyroidism, in which surgical removal of the parathyroid glands would be indicated, but is not possible in the specific case.
Animal data
Cinacalcet performs in animals with chronic renal failure
- a decrease in the synthesis and release of parathyroid hormone in the parathyroid gland,
- to an upregulation of the calcium sensitive receptor and the vitamin D receptor ,
- to a decreased proliferation of the parathyroid cells,
- reduced progression of parathyroid gland enlargement ( hyperplasia ),
- to an increased programmed cell death (apoptosis) of parathyroid cells,
- to a reduced progression of bone changes caused by increased parathyroid hormone levels ( osteitis fibrosa ) and
- decreased progression of calcium deposits in the arteries.
Human studies
In patients with primary hyperparathyroidism or in chronic hemodialysis patients , the use of cinacalcet leads to a rapid decrease in parathyroid hormone levels within 2–4 hours. In dialysis patients, but not in patients with primary hyperparathyroidism, there is a drop in serum calcium within 4–8 hours.
In primary hyperparathyroidism, long-term use of Cinacalcet leads to a slow decrease in the previously increased calcium level and an increase in the phosphate level; the parathyroid hormone levels change only slightly.
In dialysis patients, long-term use of Cinacalcet leads to an increasing decrease in parathyroid hormone, calcium and phosphate levels. The secondary hyperparathyroidism can thus be kept under control for years.
Cinacalcet lowers elevated parathyroid hormone levels in patients with stages 3 and 4 chronic renal failure . The serum calcium is lowered, the serum phosphate increases. The excretion of calcium in the urine increases and the excretion of phosphate decreases.
After kidney transplantation , persistent hyperparathyroidism leads to hypercalcemia and hypophosphataemia due to increased excretion of phosphate by the kidneys. In this situation, cinacalcet normalizes phosphate excretion and serum phosphate.
However, currently completed studies in humans are limited to the effect of Cinacalcet on so-called surrogate parameters such as parathyroid hormone, calcium and phosphate.
Studies examining the effects of therapy with Cinacalcet on clinically relevant endpoints are currently only being conducted. A study examines the effect of cinacalcet on calcification of the aortic valve in dialysis patients . A second study examines the effects of treating dialysis patients with Cinacalcet on mortality and cardiovascular endpoints such as heart attack , stroke and the like. It has not yet been clarified whether it makes sense to use Cinacalcet in patients with chronic kidney disease who do not yet require dialysis treatment.
Side effects
The most common side effects with cinacalcet are nausea and vomiting. Increasing the dose slowly can help reduce side effects.
A study on the safety of use in pediatric patients was stopped as a precaution in February 2013 after the death of a 14-year-old patient, even if it was not clear whether the drug was fatal. Possible side effects could be hypocalcemia with subsequent seizures up to glottis spasms or cardiac arrhythmias caused by prolonging the QT time, which is why it is particularly important to monitor the occurrence of hypocalcemia. Independently of this, EU approval was also granted in September 2017 for secondary hyperparathyroidism in children aged three and over.
Individual evidence
- ↑ There is not yet a harmonized classification for this substance . A label for N - [(1R) -1- (naphthalen-1-yl) ethyl] -3- [3- (trifluoromethyl) phenyl] propane-1-amine hydrochloride (1: 1) is shown, which is derived from a self-classification by the distributor ) in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on December 28, 2019.
- ↑ ROTE LISTE ® 2008, Verlag Rote Liste ® Service GmbH, Frankfurt am Main, page 52, ISBN 978-3-939192-20-6 .
- ↑ a b European Commission Approves Expanded Use Of Mimpara® (Cinacalcet) For The Treatment Of Secondary Hyperparathyroidism In Children With End-Stage Renal Disease On Dialysis , PM Amgen, August 31, 2017, accessed September 6, 2017.
- ↑ M. Chonchol, F. Locatelli, HE Abboud, C. Charytan, AL de Francisco, S. Jolly, M. Kaplan, SD Roger, S. Sarkar, MB Albizem, TC Mix, Y. Kubo, GA Block: A randomized , double-blind, placebo-controlled study to assess the efficacy and safety of cinacalcet HCl in participants with CKD not receiving dialysis. In: American journal of kidney diseases. Volume 53, Number 2, February 2009, pp. 197-207, doi : 10.1053 / j.ajkd.2008.09.021 , PMID 19110359 .
- ^ Andreas L Serra, Claudia Wuhrmann, Rudolf P Wüthrich: Phosphatemic effect of cinacalcet in kidney transplant recipients with persistent hyperparathyroidism . In: American Journal of Kidney Diseases . 52, No. 6, December 2008, pp. 1151-1157. doi : 10.1053 / j.ajkd.2008.08.012 . PMID 18950915 .
- ↑ Tilman B Drüeke, Eberhard Ritz: Treatment of secondary hyperparathyroidism in CKD patients with cinacalcet and / or vitamin D derivatives . In: Clinical Journal of the American Society of Nephrology . 4, No. 1, January 2009, pp. 234-241. doi : 10.2215 / CJN.04520908 . PMID 19056615 .
- ↑ FDA Drug Safety Communication: FDA suspends pediatric clinical trials of Sensipar (cinacalcet hydrochloride) after report of death
- ^ Red Hand Letter from Amgen in March 2013 to Mimpara Janssen. (PDF; 333 kB) Accessed February 24, 2016 .
