Continuing Education Activity

Cinacalcet is a medication used in the management and treatment of secondary hyperparathyroidism (on dialysis population), primary hyperparathyroidism for which the patient may not be a surgical candidate, and the treatment of calciphylaxis in patients with advanced kidney disease or on dialysis. It belongs to the calcimimetic class of medications. This activity reviews the indications, action, and contraindications for cinacalcet as a valuable agent in the treatment of the conditions mentioned above. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the healthcare team in the care of patients with hyperparathyroidism and related conditions.

Objectives:

• Identify the mechanism of action and administration of cinacalcet.
• Describe the adverse effects and contraindications of cinacalcet
• Review the appropriate monitoring and toxicity of cinacalcet
• Outline some interprofessional team strategies for improving care coordination and communication to advance knowledge regarding the side effects of cinacalcet and improve outcomes.

Indications

Cinacalcet hydrochloride classifies as a "calcimimetic." Its primary indication is to reduce the parathyroid hormone level in patients with secondary hyperparathyroidism associated with end-stage kidney disease. In chronic kidney disease, patients often have high phosphorus levels, variable calcium levels, and increased parathyroid hormone levels (>300 pg/mL).[1] The role of the cinacalcet in this condition is to reduce the serum parathyroid hormone level and prevent bone destruction. This intervention reinstates the calcium levels within the target ranges defined by the Kidney Disease Outcomes Quality Initiative (K-DOQI) for disease management.[2] It reduces the chances of requiring a parathyroidectomy for secondary hyperparathyroidism. Clinicians often use this medication in combination therapy with an oral phosphorous binder (calcium acetate, sevelamer) as well as Vitamin D analogs (calcitriol, paricalcitol).[1] 

Cinacalcet can be used for the treatment of primary hyperparathyroidism in the individual who is not a surgical candidate or in whom surgery would be high risk.[3] Because cinacalcet lowers PTH and reduces serum calcium levels, it can be used along with bisphosphonates to reduce calcium resorption from bone. 

Cinacalcet is often a part of the treatment modality in individuals with calciphylaxis, which can present in the patient with end-stage kidney disease.[4] It is being used increasingly in pediatric populations with CKD and suffering from concomitant renal osteodystrophy, described as CKD–mineral and bone disorders (CKD–MBD). An important part of the management of this condition is lowering of the parathyroid hormone level and treating hypercalcemia with cinacalcet as well as treating hyperphosphatemia with a non-calcium based phosphorus binder. Cinacalcet, when combined with other treatments for calciphylaxis, has shown improved efficacy in treating this condition.[4]  

Clinicians can also use this medication has also been used to treat hypercalcemia in patients with parathyroid carcinoma. While the treatment of parathyroid carcinoma is primarily surgical, but it does help in reducing the serum calcium level.[5]  It may also be a therapeutic option in patients in whom surgical removal of the mass is deemed futile.[6]

Mechanism of Action

Cinacalcet is a “calcimimetic,” meaning that it acts on the calcium-sensing receptors (CaSR) located on the chief cells of the parathyroid gland.[7] CaSR detects a minor change in the extracellular calcium level and maintains the PTH level accordingly.[7] This process occurs through PTH gene transcription and parathyroid cell growth. The CaSR couples with a 7-transmembrane domain G-proteins. On the chief cells, the predominant forms are Gi and Gq. Once activated, cAMP accumulation becomes inhibited, and simultaneously the phosphoinositide-phospholipase C pathway gets stimulated. The ensuing increase in IP3 and DAG levels leads to intracellular calcium influx. The end result of this the Gq pathway is specifically dominant-negative, i.e., suppression of PTH secretion. Disruption of this cascade has also been present in various etiologies of hyperparathyroidism.[8] “Calcimimetic” medications, as the name suggests, may not be the real calcium ligands, but they activate these receptors and utilize the Gq/Gi pathways to establish the negative feedback loop to raise calcium levels. This feedback occurs through suppression of both the production of PTH and its secretion and ultimately leads to the mitigation of calcium and phosphorus products in blood.[9]

Administration

This medication is to be taken once daily with food. Most therapies directed at the endocrine axis should be preferably taken at the same time every day. Food has a positive effect on cinacalcet's absorption, increasing its levels in the plasma by more than three-fold compared to when taking it without food.[10] It has a long half-life of approximately 1.5 days. It is highly bound to plasma proteins, metabolized primarily in the liver, and is dependent on the kidney for excretion.[10]

The dosage schedules are adapted according to the PTH response individually in patients. The pediatric population may warrant reduced dosages because of their less body surface area and the changed CYP profiles.[2]

Adverse Effects

The common side effects are nausea and vomiting.[6] It can occur in up to one-third of patients taking this medication. Dizziness, diarrhea, and decreased appetite are other side effects of this medication as well. Cinacalcet can cause hypocalcemia. The patients on this medication need to be closely followed for common symptoms associated with hypocalcemia include tingling, muscle twitching, cramps, changes in mood, or irritability. On the ECG, a prolonged QT interval may be present. Patients with a history of congenital long QT syndrome, family history of long QT syndrome, and other conditions that predispose to QT interval prolongation may be at increased risk.[10] Oversuppresion of PTH can cause adynamic bone disease. 

Contraindications

Calcium level below 8.4 milligrams per deciliter is a contraindication to initiating this medication.[10]

Monitoring

Calcium levels need to be followed closely for any patient on this medication. Patients require assessment for signs and symptoms of hypocalcemia. Individuals on this medication need monitoring for side effects, including nausea and vomiting.[10] Cinacalcet may interact with other medications such as anticholinesterase inhibitors in dementia patients. Patients with hepatic impairment and hepatic impairment should have close monitoring. 

Toxicity

There is no "toxic" level of cinacalcet. Dose-limiting effects include nausea and vomiting, which would limit or preclude its use.[10] If hypocalcemia is present, the clinician should discontinue the medication, and hypocalcemia should have treated with intravenous calcium. Other electrolyte abnormalities, including magnesium and phosphorous, also need to be monitored.[10] To date, there is not much evidence to validate cinacalcet's use or its toxicity in pregnant women. 

Enhancing Healthcare Team Outcomes

With the rise in the burden of non-communicable diseases i.e., cardiovascular and chronic kidney disease, we must refine all our non-surgical options. Cinacalcet, a calcimimetic that counteracts the increase in PTH, is gaining center stage. While instituting a multi-modality approach for calciphylaxis, chronic kidney disease, and hyperparathyroidism, this medication is one of the 'essentials' in the medical armamentarium. Nephrologists most commonly prescribe it for patients with secondary hyperparathyroidism on dialysis. Endocrinologists may prescribe it in patients with primary hyperparathyroidism in patients in whom surgical intervention is not an option or who would otherwise be too high risk for surgery. Patients need to be aware of side effects, including nausea and vomiting. They also should be educated about symptoms of hypocalcemia. Calcium levels should be monitored closely in these patients. The interprofessional healthcare team should also engage the consult of a clinical pharmacist to optimize therapeutic results and minimize adverse events.