What is Cinacalcet (calcimimetic agent)?

Cinacalcet: A Calcimimetic Agent for Secondary Hyperparathyroidism

Cinacalcet is a calcimimetic medication that directly lowers parathyroid hormone (PTH) levels by increasing the sensitivity of calcium-sensing receptors in the parathyroid glands, primarily used for secondary hyperparathyroidism in dialysis patients, but with limited effects on mortality outcomes. 1

Mechanism of Action

Cinacalcet works through a unique mechanism compared to other treatments for hyperparathyroidism:

• Acts as a positive modulator of calcium-sensing receptors on the surface of parathyroid chief cells 2
• Increases sensitivity of these receptors to extracellular calcium, suppressing PTH secretion 2
• Reduces PTH without increasing calcium and phosphorus levels 1
• The reduction in PTH is associated with a concomitant decrease in serum calcium levels 2

FDA-Approved Indications

Cinacalcet is approved for:

• Secondary hyperparathyroidism in adult patients with chronic kidney disease (CKD) on dialysis 1
• Hypercalcemia in patients with parathyroid carcinoma 1
• Primary hyperparathyroidism in patients who cannot undergo parathyroidectomy 1

Clinical Efficacy

The evidence for cinacalcet shows mixed results depending on the outcome measured:

• Reduction in PTH levels: Cinacalcet effectively reduces PTH levels in secondary hyperparathyroidism, with approximately 46-65% of patients achieving significant reductions 3
• Prevention of parathyroidectomy: Provides a relative risk reduction of 51% (RR 0.49) for preventing surgical parathyroidectomy 4
• Hypercalcemia management: Reduces the risk of hypercalcemia with a relative risk of 0.23 4
• Mortality outcomes: Has little or no effect on all-cause mortality (RR 0.97) 4
• Cardiovascular mortality: Effects remain uncertain with imprecise data (RR 0.67) 4

Pharmacokinetics

Key pharmacokinetic properties include:

• Oral bioavailability: 20-25% 5
• Peak plasma concentration: Reached within 2-6 hours after administration 2
• Half-life: 30-40 hours (terminal elimination) 2
• Steady state: Achieved within 7 days of consistent dosing 2
• Metabolism: Primarily through CYP3A4, CYP2D6, and CYP1A2 enzymes 2
• Excretion: 80% in urine, 15% in feces (primarily as metabolites) 2

Adverse Effects

Common adverse effects include:

• Hypocalcemia: Significantly increased risk (RR 6.98) 4
• Gastrointestinal effects: Nausea (RR 2.02), vomiting (RR 1.97), and diarrhea 4
• Most side effects are mild to moderate in severity and often transient 3

Dosing Considerations

• Starting dose: 30 mg once daily 1
• Dose titration: Sequential increases to 60,90,120, and 180 mg once daily as needed 1
• Titration frequency: No more frequently than every 2-4 weeks 1
• Monitoring: Serum calcium, phosphate, and PTH every 4 weeks for first 3 months, then monthly 1

Clinical Implications and Limitations

• Cinacalcet has become one of the most expensive drug costs for dialysis patients in the US, despite limited evidence for improved mortality outcomes 4
• The medication should be used primarily for its FDA-approved indications rather than for routine use in all CKD patients 1
• Benefits appear limited to preventing parathyroidectomy and managing hypercalcemia in specific patient populations 4
• Patients with moderate to severe hepatic impairment require close monitoring due to increased drug exposure 2

Treatment Algorithm

1. First-line therapy for secondary hyperparathyroidism should focus on vitamin D therapy and phosphate binders 1
2. Consider cinacalcet when:
   • Patient is on dialysis with elevated PTH despite optimized vitamin D therapy
   • Patient has normal or high serum calcium concentration
   • Surgical parathyroidectomy is contraindicated due to risks outweighing benefits 1
3. Consider parathyroidectomy for:
   • Persistent hypercalcemic hyperparathyroidism despite optimized medical therapy
   • Severe hyperparathyroidism with hypercalcemia/hyperphosphatemia refractory to medical therapy 1

In conclusion, cinacalcet represents an important therapeutic option for specific hyperparathyroidism scenarios, but its use should be targeted rather than routine, given its significant side effect profile and limited impact on mortality outcomes.