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Monday, August 11, 2025

Calcimimetics


1. Introduction

  • Calcimimetics are a class of agents that mimic the action of calcium on tissues by allosterically activating the calcium-sensing receptor (CaSR) on the parathyroid gland.

  • Their activation of CaSR lowers parathyroid hormone (PTH) secretion, leading to a reduction in serum calcium and phosphate levels.

  • Used primarily in the management of secondary hyperparathyroidism (SHPT) associated with chronic kidney disease (CKD) and parathyroid carcinoma.

  • Main agents: Cinacalcet (oral) and Etelcalcetide (intravenous).

2. Mechanism of Action

  • CaSR is a G-protein coupled receptor found mainly on parathyroid chief cells.

  • Under normal physiology, high serum calcium binds to CaSR → inhibits PTH secretion.

  • Calcimimetics bind allosterically to CaSR → increase its sensitivity to extracellular calcium → stronger suppression of PTH secretion at lower calcium levels.

  • Leads to:

    • Decreased bone resorption (indirect).

    • Lower serum calcium and phosphate (due to reduced PTH).

3. Pharmacological Agents

A. Cinacalcet

  • Oral calcimimetic; first agent in this class.

  • Brand names: Sensipar (US), Mimpara (EU).

B. Etelcalcetide

  • Intravenous calcimimetic; administered thrice weekly at the end of hemodialysis.

  • Brand name: Parsabiv.

4. Pharmacokinetics

Cinacalcet

  • Absorption: well absorbed orally; peak plasma levels in 2–6 hours.

  • Distribution: highly protein-bound (>90%).

  • Metabolism: extensively via CYP3A4, CYP2D6, CYP1A2.

  • Elimination half-life: ~30–40 hours.

Etelcalcetide

  • Administration: IV bolus post-hemodialysis.

  • Distribution: binds to serum albumin via disulfide bonds.

  • Metabolism: degraded by proteolysis.

  • Elimination half-life: ~3–5 days (allows thrice-weekly dosing).

5. Therapeutic Indications

A. Cinacalcet

  • Secondary hyperparathyroidism in adult CKD patients on dialysis.

  • Hypercalcemia in parathyroid carcinoma.

  • Severe primary hyperparathyroidism in patients who are not surgical candidates.

B. Etelcalcetide

  • Secondary hyperparathyroidism in adult CKD patients on hemodialysis.

6. Contraindications

  • Hypocalcemia (serum calcium below lower normal limit).

  • Known hypersensitivity to the drug or its components.

7. Adverse Effects

Common

  • Nausea, vomiting, diarrhea.

  • Hypocalcemia-related symptoms: muscle cramps, paresthesia.

Serious

  • Severe hypocalcemia → seizures, arrhythmias, hypotension.

  • QT interval prolongation secondary to hypocalcemia.

  • Adynamic bone disease with chronic excessive suppression of PTH.

8. Drug Interactions

Cinacalcet

  • CYP2D6 substrates (e.g., tricyclic antidepressants, flecainide, metoprolol) – may require dose adjustment due to CYP2D6 inhibition.

  • CYP3A4 inhibitors (e.g., ketoconazole, erythromycin) – increase cinacalcet levels.

  • CYP3A4 inducers (e.g., rifampin, carbamazepine) – decrease cinacalcet levels.

Etelcalcetide

  • Minimal CYP450-mediated interactions; however, additive hypocalcemia possible with other calcium-lowering drugs.

9. Monitoring

  • Serum calcium: before initiation, within 1 week of starting or adjusting dose, and regularly thereafter.

  • Serum phosphate and PTH levels: periodically to assess treatment response and avoid oversuppression.

  • ECG monitoring in patients at risk for QT prolongation.

10. Special Precautions

  • Gradual dose titration to avoid severe hypocalcemia.

  • Avoid abrupt discontinuation to prevent rebound hyperparathyroidism.

  • Use cautiously in patients with seizure disorders (risk increases with hypocalcemia).

  • In pediatric patients, safety and efficacy are not well established (except certain approved uses in adolescents in some regions).

11. Advantages and Limitations

Advantages

  • Effective in lowering PTH without causing hypercalcemia or hyperphosphatemia (unlike vitamin D analogs).

  • Etelcalcetide provides post-dialysis dosing, improving adherence in HD patients.

  • Can be used when surgery is not possible for parathyroid carcinoma or primary hyperparathyroidism.

Limitations

  • GI intolerance is common, especially with cinacalcet.

  • Requires frequent calcium monitoring to prevent hypocalcemia.

  • Does not address underlying cause in primary hyperparathyroidism (only palliative if surgery not an option).




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