Cinacalcet Hydrochloride

Mechanism

Pharmacological Class and Group

Type II calcimimetic (Positive allosteric modulator of the calcium sensing receptor).

Mechanism of Action

The secretion of parathyroid hormone (PTH) by the chief cells of the parathyroid gland is tightly regulated by the concentration of extracellular free calcium ions. This physiological sensing is mediated by the transmembrane G protein-coupled calcium sensing receptor (CaSR).

CaSR Allosteric Modulation Mechanism

1. Binding to the Transmembrane Domain of CaSR: Cinacalcet selectively binds to a specific allosteric target within the hydrophobic seven-helix transmembrane domain of CaSR.

2. Increased Sensitivity to Extracellular Calcium: Its coupling induces a stable conformational change in the CaSR that remarkably increases the affinity of the receptor for extracellular free calcium ions present in the circulation:

Cinacalcet CaSR sensitization Receptor activation at lower Ca²⁺ concentrations

3. Inhibitory Intracellular Signaling (G_i and G_q): Sustained activation of the receptor modulates the intracellular signaling cascade of phospholipase C and inhibits adenylate cyclase.

4. Rapid Suppression of PTH Secretion: This stops the exocytosis of PTH granules and suppresses the de novo synthesis of parathyroid hormone within a few minutes of taking it, consequently reducing pathological bone resorption, hypercalcemia and associated hyperphosphatemia.

Pharmacokinetics

High Resolution Pharmacokinetics

• Absorption and Bioavailability: Rapid absorption. Absolute bioavailability around 20-25%. Administration together with high-fat foods substantially increases the area under the curve (AUC) by up to 82%.
• Distribution: Very large apparent volume of distribution (approximately 1000 L). Extreme nonspecific binding to circulating plasma proteins (97%).
• Metabolism: Extensive phase I oxidative hepatic metabolism mediated mixed by cytochromes CYP3A4, CYP2D6 and CYP1A2. It generates multiple inactive metabolites with rapid secondary elimination.
• Excretion: Elimination of 80% as inactive metabolites through the kidneys (urine) and 20% through feces and bile.
• Half-life (t_1/2): Prolonged biphasic elimination half-life, with a terminal clearance phase of between 30 and 40 hours. Allows dosing once a day.

Indicators and dose

Clinical Indications and Off-Label Uses

• Chronic Secondary Hyperparathyroidism (HPT2): In adult patients with end-stage chronic kidney disease being treated with maintenance dialysis therapy.
• Severe hypercalcemia secondary to Parathyroid Carcinoma: Net and rapid reduction in tumor plasma calcium.
• Symptomatic Primary Hyperparathyroidism (HPT1): In patients where surgical thyroidectomy/parathyroidectomy is indicated but clinically not feasible due to severe pre-anesthetic risks or comorbidities.

Dosage and Clinical Adjustment

Secondary hyperparathyroidism (HPT2) on dialysis:

• Initial Dose: 30 mg once a day orally. It should be taken strictly with the main meal or immediately after to maximize bioavailability and mitigate nausea.
• Dose Titration: Evaluate levels of intact PTH (iPTH) and corrected calcium 2-4 weeks after initiation. Increase in progressive steps to 60 mg, 90 mg, 120 mg and up to a maximum limit of 180 mg once daily to maintain iPTH levels within the recommended target range (150-300 pg/mL).

Parathyroid Carcinoma / Refractory Primary HPT:

• Starting dose of 30 mg twice a day, which can be adjusted biweekly to 60 mg, 90 mg twice a day, up to a therapeutic maximum of 90 mg 3 to 4 times a day depending on serum calcium levels.

Adjustment in Renal Failure: No specific dose adjustment is required. Cinacalcet is designed primarily for patients on end-stage chronic dialysis.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Hypersensitivity to cinacalcet.
• Uncorrected baseline hypocalcemia: Corrected serum total calcium levels < 8.4 mg/dL (the drug massively worsens hypocalcemia).

Relative Contraindications

• History of generalized seizures or refractory epilepsy (induced hypocalcemia depresses the seizure threshold, triggering seizures).
• Moderate-severe hepatic insufficiency Child-Pugh B or C, due to the net lengthening of the drug's elimination half-life.

Adverse Effects (ADR) and Specific Toxicity

• Very common (>10%): Persistent nausea, explosive vomiting (ADR very limiting for drug adherence, of probable origin mediated by CaSR receptors of the upper gastrointestinal tract).
• Frequent (1%-10%): Anorexia, generalized myalgia, distal paresthesias in hands and feet (classic sign of mild hypocalcemia), dizziness, headache, gastric dyspepsia, decreased levels of circulating testosterone.
• Rare: Severe symptomatic hypocalcemia (total corrected serum calcium < 7.5 mg/dL), secondary prolongation of the cardiac corrected QT (QTc) interval leading to torsade de pointes arrhythmias.

Critical Toxicity: Severe Hypocalcemia and Tetany Syndrome

The acute decrease in plasma extracellular free calcium levels alters the electrophysiological stability of neuronal and muscle membranes, inducing extreme progressive neuro-motor hyperexcitability. The patient presents painful involuntary carpopedal spasms when inflating the sphygmomanometer (Trousseau's sign) or sudden contraction of the ipsilateral muscles of the face when percussing the facial nerve in front of the auditory canal (Chvostek's sign).

Corrected serum calcium < 7.5 mg/dL Perioral and acral paresthesias Tetany and Laryngospasm

In advanced cases it presents with refractory laryngospasm with compromise of the upper airway, seizures and cardiac arrhythmias with prolongation of the QT interval. It is mandatory to determine the corrected serum calcium before starting the drug, weekly at the beginning and periodically. If it drops below 8.4 mg/dL, supplementation with calcium and calcitriol should be started and cinacalcet should be temporarily suspended.

Drug Interactions of Clinical Relevance

• Strong CYP3A4 inhibitors (Ketoconazole, Itraconazole, Ritonavir): They double the serum levels of circulating cinacalcet, requiring clinical monitoring and maintenance dose reduction.
• Drugs metabolized exclusively by narrow-range CYP2D6 (Flecainide, Propafenone, Tricyclic antidepressants): Cinacalcet is a potent inhibitor of the CYP2D6 enzyme, significantly increasing the circulating concentrations and half-life of these drugs.

Safety in Pregnancy and Breastfeeding

• Pregnancy: Not recommended. It crosses transplacentally in preclinical studies and is associated with neonatal hypocalcemia and rebound parathyroid hypoplasia in the offspring.
• Breastfeeding: Contraindicated. It is actively excreted in breast milk. Neonatal safety is unknown.