Etelcalcetide

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Etelcalcetide
Etelcalcetide.svg
Clinical data
Trade names Parsabiv
Other namesVelcalcetide, telcalcetide, AMG-416, KAI-4169, ONO-5163
AHFS/Drugs.com Monograph
MedlinePlus a617011
License data
Routes of
administration 		Intravenous injection
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life 3–5 days in dialysis patients
Excretion 60% in dialysate, 7% in urine and faeces
Identifiers
  • (6R,9R,12R,15R,18R,21R,24S,29R)-24-Acetamido-1,29-diamino-12,15,18-tris(3-carbamimidamidopropyl)-6-carbamoyl-1-imino-9,21-dimethyl-8,11,14,17,20,23-hexaoxo-26,27-dithia-2,7,10,13,16,19,22-heptaazatria contan-30-oic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C38H73N21O10S2
Molar mass 1048.26 g·mol−1
3D model (JSmol)
  • C[C@H](C(=O)N[C@H](CCCNC(=N)N)C(=O)N)NC(=O)[C@@H](CCCNC(=N)N)NC(=O)[C@@H](CCCNC(=N)N)NC(=O)[C@@H](CCCNC(=N)N)NC(=O)[C@@H](C)NC(=O)[C@@H](CSSC[C@@H](C(=O)O)N)NC(=O)C
  • InChI=1S/C38H73N21O10S2/c1-18(28(62)56-22(27(40)61)8-4-12-49-35(41)42)53-30(64)23(9-5-13-50-36(43)44)58-32(66)25(11-7-15-52-38(47)48)59-31(65)24(10-6-14-51-37(45)46)57-29(63)19(2)54-33(67)26(55-20(3)60)17-71-70-16-21(39)34(68)69/h18-19,21-26H,4-17,39H2,1-3H3,(H2,40,61)(H,53,64)(H,54,67)(H,55,60)(H,56,62)(H,57,63)(H,58,66)(H,59,65)(H,68,69)(H4,41,42,49)(H4,43,44,50)(H4,45,46,51)(H4,47,48,52)/t18-,19-,21+,22-,23-,24-,25-,26-/m1/s1
  • Key:ANIAZGVDEUQPRI-ZJQCGQFWSA-N

  • as salt: InChI=1S/C38H73N21O10S2.ClH/c1-18(28(62)56-22(27(40)61)8-4-12-49-35(41)42)53-30(64)23(9-5-13-50-36(43)44)58-32(66)25(11-7-15-52-38(47)48)59-31(65)24(10-6-14-51-37(45)46)57-29(63)19(2)54-33(67)26(55-20(3)60)17-71-70-16-21(39)34(68)69;/h18-19,21-26H,4-17,39H2,1-3H3,(H2,40,61)(H,53,64)(H,54,67)(H,55,60)(H,56,62)(H,57,63)(H,58,66)(H,59,65)(H,68,69)(H4,41,42,49)(H4,43,44,50)(H4,45,46,51)(H4,47,48,52);1H/t18-,19-,21+,22-,23-,24-,25-,26-;/m1./s1
  • Key:KHQMSZGKHGQUHG-WZDHWKSBSA-N

Etelcalcetide, sold under the brand name Parsabiv, is a calcimimetic medication for the treatment of secondary hyperparathyroidism in people undergoing hemodialysis. It is administered intravenously at the end of each dialysis session. [3] [4] Etelcalcetide functions by binding to and activating the calcium-sensing receptor in the parathyroid gland. [3] Parsabiv is currently owned by Amgen and Ono Pharmaceuticals in Japan. [5] [6]

Contents

Medical uses

Etelcalcetide is used for the treatment of secondary hyperparathyroidism in people with chronic kidney disease (CKD) on hemodialysis. [7] Hyperparathyroidism is the condition of elevated parathyroid hormone (PTH) levels and is often observed in people with CKD. [8]

Pharmacodynamics

Mechanism of action

Etelcalcetide functions by binding to and activating the calcium-sensing receptor (CaSR) in the parathyroid gland as an allosteric activator, resulting in PTH reduction and suppression. [3]

Pharmacokinetics

Etelcalcetide functions in a first order elimination, with a half life of 19 hours. [6]

No interaction studies in humans were conducted. Studies in vitro showed no affinity of etelcalcetide to cytochrome P450 enzymes or common transport proteins. Therefore, no relevant pharmacokinetic interactions are expected. [7] [9]

Side effects

Common side effects (in more than 10% of people) are nausea, vomiting, diarrhoea, muscle spasms, and hypocalcaemia (too low blood calcium levels). In clinical studies, the latter side effect was usually mild to moderate and without symptoms. An increase of the QT interval of more than 60  ms was detected in 1.2% of people receiving etelcalcetide. [7] [9]

Due to the lower iPTH levels achieved by the use of this drug, it is possible that adynamic bone disease could occur at levels "below 100 pg/mL" [6]

Contraindications

The drug is contraindicated in people with blood serum calcium levels below the norm. [7] [9]

Chemistry

The substance is a peptide consisting mostly of D-amino acids instead of the common L-amino acids. More specifically, it is the disulfide of N-acetyl-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-D-argininamide with L-cysteine. [10]

History

Originally, Etelcalcetide was being developed by KAI Pharmaceuticals. After positive phase II trials, Amgen acquired KAI for $315 million. [11]

In 2011, KAI entered into agreement with Ono Pharmaceutical for production of Etelcalcetide in Japan, the deal being worth ¥1 billion. [6]

In August 2015 Amgen Inc. announced its submission of a new drug application to the Food and Drug Administration for etelcalcetide. [3] The European Medicines Agency approved the medication in November 2016. [7]

In February 2017, the FDA approved Parsabiv for the treatment of secondary hyperparathyroidism. [12]

Research

Phase II trials found that Etelcalcetide was able to lower PTH levels in one cohort by -49% vs a 29% increase in the placebo group. [6] In another phase II study "89% of patients experienced a C30% reduction in PTH and 56% achieved a PTH level of B300 pg/mL." [6]

In 2017, two phase III trials found that using etelcalcetide showed greater symptom reduction compared to placebo. [13] Etelcalcetide was also able to lower PTH levels below 300pg/mL more often. [13]

Phase I pediatric studies are planned for the US and UK for etelcalcetide. [6]

Related Research Articles

<span class="mw-page-title-main">Parathyroid hormone</span> Mammalian protein found in humans

Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates the serum calcium concentration through its effects on bone, kidney, and intestine.

Hypercalcemia, also spelled hypercalcaemia, is a high calcium (Ca2+) level in the blood serum. The normal range is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L defined as hypercalcemia. Those with a mild increase that has developed slowly typically have no symptoms. In those with greater levels or rapid onset, symptoms may include abdominal pain, bone pain, confusion, depression, weakness, kidney stones or an abnormal heart rhythm including cardiac arrest.

<span class="mw-page-title-main">Hyperparathyroidism</span> Increase in parathyroid hormone levels in the blood

Hyperparathyroidism is an increase in parathyroid hormone (PTH) levels in the blood. This occurs from a disorder either within the parathyroid glands or as response to external stimuli. Symptoms of hyperparathyroidism are caused by inappropriately normal or elevated blood calcium excreted from the bones and flowing into the blood stream in response to increased production of parathyroid hormone. In healthy people, when blood calcium levels are high, parathyroid hormone levels should be low. With long-standing hyperparathyroidism, the most common symptom is kidney stones. Other symptoms may include bone pain, weakness, depression, confusion, and increased urination. Both primary and secondary may result in osteoporosis.

<span class="mw-page-title-main">Hyperphosphatemia</span> Medical condition

Hyperphosphatemia is an electrolyte disorder in which there is an elevated level of phosphate in the blood. Most people have no symptoms while others develop calcium deposits in the soft tissue. Often there is also low calcium levels which can result in muscle spasms.

<span class="mw-page-title-main">Parathyroidectomy</span> Surgical removal of one or more of the parathyroid glands

Parathyroidectomy is the surgical removal of one or more of the (usually) four parathyroid glands. This procedure is used to remove an adenoma or hyperplasia of these glands when they are producing excessive parathyroid hormone (PTH): hyperparathyroidism. The glands are usually four in number and located adjacent to the posterior surface of the thyroid gland, but their exact location is variable. When an elevated PTH level is found, a sestamibi scan or an ultrasound may be performed in order to confirm the presence and location of abnormal parathyroid tissue.

<span class="mw-page-title-main">Cinacalcet</span> Chemical compound

Cinacalcet, sold under the brand name Sensipar among others, is a medication used to treat primary hyperparathyroidism, tertiary hyperparathyroidism and parathyroid carcinoma. Cinacalcet acts as a calcimimetic by allosteric activation of the calcium-sensing receptor that is expressed in various human organ tissues.

Renal osteodystrophy is currently defined as an alteration of bone morphology in patients with chronic kidney disease (CKD). It is one measure of the skeletal component of the systemic disorder of chronic kidney disease-mineral and bone disorder (CKD-MBD). The term "renal osteodystrophy" was coined in 1943, 60 years after an association was identified between bone disease and kidney failure.

<span class="mw-page-title-main">Primary hyperparathyroidism</span> Medical condition

Primary hyperparathyroidism is a medical condition where the parathyroid gland produce excess amounts of parathyroid hormone (PTH). The symptoms of the condition relate to the resulting elevated serum calcium (hypercalcemia), which can cause digestive symptoms, kidney stones, psychiatric abnormalities, and bone disease.

<span class="mw-page-title-main">Osteitis fibrosa cystica</span> Medical condition

Osteitis fibrosa cystica is a skeletal disorder resulting in a loss of bone mass, a weakening of the bones as their calcified supporting structures are replaced with fibrous tissue, and the formation of cyst-like brown tumors in and around the bone. Osteitis fibrosis cystica (OFC), also known as osteitis fibrosa, osteodystrophia fibrosa, and von Recklinghausen's disease of bone, is caused by hyperparathyroidism, which is a surplus of parathyroid hormone from over-active parathyroid glands. This surplus stimulates the activity of osteoclasts, cells that break down bone, in a process known as osteoclastic bone resorption. The hyperparathyroidism can be triggered by a parathyroid adenoma, hereditary factors, parathyroid carcinoma, or renal osteodystrophy. Osteoclastic bone resorption releases minerals, including calcium, from the bone into the bloodstream, causing both elevated blood calcium levels, and the structural changes which weaken the bone. The symptoms of the disease are the consequences of both the general softening of the bones and the excess calcium in the blood, and include bone fractures, kidney stones, nausea, moth-eaten appearance in the bones, appetite loss, and weight loss.

<span class="mw-page-title-main">Secondary hyperparathyroidism</span> Medical condition

Secondary hyperparathyroidism is the medical condition of excessive secretion of parathyroid hormone (PTH) by the parathyroid glands in response to hypocalcemia, with resultant hyperplasia of these glands. This disorder is primarily seen in patients with chronic kidney failure. It is sometimes abbreviated "SHPT" in medical literature.

<span class="mw-page-title-main">Tertiary hyperparathyroidism</span> Medical condition

Tertiary hyperparathyroidism is a condition involving the overproduction of the hormone, parathyroid hormone, produced by the parathyroid glands. The parathyroid glands are involved in monitoring and regulating blood calcium levels and respond by either producing or ceasing to produce parathyroid hormone.

<span class="mw-page-title-main">Milk-alkali syndrome</span> Medical condition

Milk-alkali syndrome (MAS), also referred to as calcium-alkali syndrome, is the third most common cause of hypercalcemia. Milk-alkali syndrome is characterized by elevated blood calcium levels, metabolic alkalosis, and acute kidney injury.

<span class="mw-page-title-main">Calcium-sensing receptor</span> Mammalian protein found in humans

The calcium-sensing receptor (CaSR) is a Class C G-protein coupled receptor which senses extracellular levels of calcium ions. It is primarily expressed in the parathyroid gland, the renal tubules of the kidney and the brain. In the parathyroid gland, it controls calcium homeostasis by regulating the release of parathyroid hormone (PTH). In the kidney it has an inhibitory effect on the reabsorption of calcium, potassium, sodium, and water depending on which segment of the tubule is being activated.

<span class="mw-page-title-main">Parathyroid carcinoma</span> Medical condition

Parathyroid carcinoma is a rare cancer resulting in parathyroid adenoma to carcinoma progression. It forms in tissues of one or more of the parathyroid glands.

<span class="mw-page-title-main">Parathyroid disease</span> Medical condition

Many conditions are associated with disorders of the function of the parathyroid gland. Some disorders may be purely anatomical resulting in an enlarged gland which will raise concern. Such benign disorders, such as parathyroid cyst, are not discussed here. Parathyroid diseases can be divided into those causing hyperparathyroidism, and those causing hypoparathyroidism.

A calcimimetic is a pharmaceutical drug that mimics the action of calcium on tissues, by allosteric activation of the calcium-sensing receptor that is expressed in various human organ tissues. Calcimimetics are used to treat secondary hyperparathyroidism (SHPT).

Sucroferric oxyhydroxide, sold under the brand name Velphoro, is a non-calcium, iron-based phosphate binder used for the control of serum phosphorus levels in adults with chronic kidney disease (CKD) on haemodialysis (HD) or peritoneal dialysis (PD). It is used in form of chewable tablets.

Recombinant human parathyroid hormone, sold under the brand name Preotact among others, is an artificially manufactured form of the parathyroid hormone used to treat hypoparathyroidism. Recombinant human parathyroid hormone is used in the treatment of osteoporosis in postmenopausal women at high risk of osteoporotic fractures. A significant reduction in the incidence of vertebral fractures has been demonstrated. It is used in combination with calcium and vitamin D supplements.

Chronic kidney disease–mineral and bone disorder (CKD–MBD) is one of the many complications associated with chronic kidney disease. It represents a systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following:

<span class="mw-page-title-main">Upacicalcet</span> Chemical compound

Upacicalcet is a drug used to treat secondary hyperparathyroidism (SHPT) - a disease of the parathyroid gland - in dialysis patients. It was approved as Upasita in Japan in June 2021. The drug is given intravenously. The active ingredient is used in the form of its sodium salt.

References

  1. ↑ "Parsabiv- etelcalcetide injection, solution". DailyMed. 17 February 2021. Retrieved 13 June 2024.
  2. ↑ "Parsabiv EPAR". European Medicines Agency. 11 November 2016. Retrieved 13 June 2024.
  3. 1 2 3 4 "Amgen Submits New Drug Application For Novel Intravenous Calcimimetic Etelcalcetide (AMG 416)"
  4. ↑ Martin KJ, Bell G, Pickthorn K, Huang S, Vick A, Hodsman P, et al. (February 2014). "Velcalcetide (AMG 416), a novel peptide agonist of the calcium-sensing receptor, reduces serum parathyroid hormone and FGF23 levels in healthy male subjects". Nephrology, Dialysis, Transplantation. 29 (2): 385–92. doi:10.1093/ndt/gft417. PMC   3910343 . PMID   24235081.
  5. ↑ "Parsabiv New FDA Drug Approval | CenterWatch". www.centerwatch.com. Retrieved 30 October 2017.
  6. 1 2 3 4 5 6 7 Blair HA (December 2016). "Etelcalcetide: First Global Approval". Drugs. 76 (18): 1787–1792. doi:10.1007/s40265-016-0671-3. PMID   27900648. S2CID   45000617.
  7. 1 2 3 4 5 "Parsabiv: EPAR – Product Information" (PDF). European Medicines Agency. 24 November 2016.
  8. ↑ Wu Q, Lai X, Zhu Z, Hong Z, Dong X, Wang T, et al. (August 2015). "Evidence for Chronic Kidney Disease-Mineral and Bone Disorder Associated With Metabolic Pathway Changes". Medicine. 94 (32): e1273. doi:10.1097/MD.0000000000001273. PMC   4616673 . PMID   26266360.
  9. 1 2 3 Haberfeld, H, ed. (2016). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  10. ↑ "Etelcalcetide". ChemSpider . Retrieved 7 January 2016.
  11. ↑ "Amgen - Investors - Press Release". investors.amgen.com. Retrieved 30 October 2017.
  12. ↑ "Parsabiv (etelcalcetide) Injection". www.accessdata.fda.gov. Retrieved 30 October 2017.
  13. 1 2 "Drug and Device News". P & T. 42 (4): 223–265. April 2017. PMC   5358678 . PMID   28381913.
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