Calcimimetics

Calcimimetics are medications that mimic the action of calcium on tissues, particularly in the parathyroid gland. By activating calcium-sensing receptors, calcimimetics inhibit the release of parathyroid hormone. Due to this mechanism, this drug class is mainly indicated for management of hyperparathyroidism. Adverse effects include hypocalcemia, GI symptoms, adynamic bone disease, and QT prolongation. Cinacalcet is metabolized by the cytochrome P450 (CYP450) system, which results in several drug interactions.

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Pharmacodynamics

Medications in the class

  • Cinacalcet: 1st drug in the class
  • Etelcalcetide: recently approved

Mechanism of action

  • Calcium-sensing receptor (CaSR):
    • G-protein-coupled receptor 
    • Responds to alterations in extracellular calcium concentrations
    • Examples: 
      • ↓ Serum calcium → parathyroid hormone (PTH) release → calcium release from bone
      • ↑ Serum calcium → ↑ calcium binding on CaSR → PTH release is inhibited
  • Calcimimetics activate CaSR on the parathyroid gland → inhibit PTH secretion
  • This leads to:
    • ↓ Serum calcium
    • ↓ Serum phosphorus

Physiologic effects

Calcimimetics prevent the progression of bone disease and adverse effects associated with hyperparathyroidism.

Pharmacokinetics

Absorption

  • Cinacalcet
    • Given orally
    • Rapidly absorbed
    • Food increases absorption.
  • Etelcalcetide: given intravenously

Distribution and metabolism

  • Cinacalcet: 
    • Highly protein bound
    • Metabolized by the cytochrome P450 (CYP450) system
  • Etelcalcetide:
    • Forms conjugates with albumin
    • Not metabolized by CYP450 enzymes

Excretion

  • Cleared renally
  • ↓ Clearance in patients with renal disease

Indications

  • Cinacalcet:
    • Primary hyperparathyroidism 
    • Secondary hyperparathyroidism: 
      • In patients with chronic kidney disease (on dialysis)
      • Studies suggest a ↓ risk of fractures
    • Parathyroid carcinoma: treatment of hypercalcemia
  • Etelcalcetide: secondary hyperparathyroidism in patients with CKD on hemodialysis

Adverse Effects and Contraindications

Adverse effects

Important adverse effects for the calcimimetic class include:

  • Hypocalcemia (more common with etelcalcetide)
  • Nausea and vomiting 
  • Diarrhea 
  • Dizziness
  • Prolonged QTc on ECG
  • Adynamic bone disease (↓ bone turnover due to chronic PTH suppression)

Contraindications

  • Hypersensitivity to the drug or its components
  • Serum calcium < the lower limit of the normal

Drug interactions

  • Cinacalcet may cause interactions through CYP450:
    • ↑ Concentrations of:
      • Propranolol and carvedilol
      • Risperidone and haloperidol
      • Amitriptyline and nortriptyline
      • Amphetamines
      • Doxorubicin
    • ↓ Concentrations of:
      • Tamoxifen
      • Tacrolimus
  • Etelcalcetide: denosumab can ↑ the hypocalcemic effect

Monitoring

Calcium levels should be monitored.

Comparison of Drug Classes

Table: Comparison of drug classes used in the management of hyperparathyroidism
Drug classMechanism of actionIndicationsAdverse effetcs
Bisphosphonates↓ Bone resorptionImprove BMD in primary hyperparathyroidism
  • Hypocalcemia
  • Hypophosphatemia
  • Esophagitis
  • Avascular necrosis
  • Osteonecrosis of the jaw
Calcimimetics
  • Mimic calcium’s effect on CaSR
  • ↓ PTH release
Hyperparathyroidism with hypercalcemia
  • Hypocalcemia
  • GI effects
  • QT prolongation
  • Adynamic bone disease
BMD: bone mineral density
VDR: vitamin D receptors

References

  1. Cinacalcet (Drug information). UpToDate. https://www.uptodate.com/contents/cinacalcet-drug-information
  2. Etelcalcetide (Drug information). UpToDate. https://www.uptodate.com/contents/etelcalcetide-drug-information
  3. Pereira, L, Meng, C, Marques, D, & Frazao, JM. (2018). Old and new calcimimetics for treatment of secondary hyperparathyroidism: Impact on biochemical and relevant clinical outcomes. Clinical Kidney Journal. Oxford Academic. https://academic.oup.com/ckj/article/11/1/80/4711103
  4. Etelcalcetide (Rx). Medscape. https://reference.medscape.com/drug/parsabiv-etalcalcetide-1000092#0
  5. Urena, P, Legoupil, N, & De Vernejoul, MC. (2005). Calcimimetics, mechanism of action, and therapeutic applications. NCBI. Pubmed.gov. https://pubmed.ncbi.nlm.nih.gov/16334889/
  6. Goodman, WG. (2002). Calcimimetic agents and secondary hyperparathyroidism: Treatment and prevention” Nephrology Dialysis Transplantation. 17: 204–207. https://web.archive.org/web/20051222021025/http://ndt.oxfordjournals.org/cgi/content/full/17/2/204
  7. Silverberg, SJ, & Fuleihan, GE. (2019). Primary hyperparathyroidism: Management. In Mulder, J.E. (Ed.), UpToDate. Retrieved July 4, 2021, from https://www.uptodate.com/contents/primary-hyperparathyroidism-management
  8. Quarles, LD, & Berkoben, M. (2021). Management of secondary hyperparathyroidism in adult dialysis patients. In Motwani, S. (Ed.), UpToDate. Retrieved July 4, 2021, from https://www.uptodate.com/contents/management-of-secondary-hyperparathyroidism-in-adult-dialysis-patients
  9. Junaid, Z, & Patel, J. (2020). Cinacalcet. [Online] StatPearls. Retrieved July 4, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK557658/

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