How does cinacalcet work in patients with chronic kidney disease?

Mechanism of Action of Cinacalcet

Cinacalcet is a calcimimetic agent that directly lowers parathyroid hormone (PTH) by increasing the sensitivity of the calcium-sensing receptor (CaSR) on parathyroid chief cells to extracellular calcium, resulting in suppressed PTH secretion and concomitant decreases in serum calcium levels. 1

Molecular Pharmacology

• Cinacalcet acts as a positive allosteric modulator of the calcium-sensing receptor, mimicking the action of calcium on these receptors located on the surface of parathyroid chief cells 2, 1

• The drug binds to the CaSR and increases its sensitivity to activation by extracellular calcium, which is the principal regulator of PTH synthesis and secretion 1

• This mechanism differs fundamentally from vitamin D compounds (which were previously the mainstay of therapy) and phosphate binders, as cinacalcet directly targets the calcium-sensing mechanism rather than attempting to correct mineral abnormalities indirectly 2

Biochemical Effects in CKD Patients

PTH Reduction:

• Cinacalcet produces substantial reductions in intact PTH levels, with a mean difference of -281 ng/L (95% CI, -326 to -236) compared to placebo 2
• The nadir in iPTH occurs approximately 2-6 hours post-dose, corresponding with maximum plasma concentration (Cmax) of cinacalcet 1
• In clinical trials, 46% of patients achieved mean iPTH levels ≤300 pg/mL compared to only 9% with placebo 2

Calcium Effects:

• Cinacalcet decreases serum calcium concentrations with a mean difference of -0.22 mmol/L (95% CI, -0.25 to -0.19) 2
• The reduction in PTH is directly associated with concomitant decreases in serum calcium levels 1
• Steady-state serum calcium concentrations remain constant over the dosing interval once achieved (within 7 days of dose change) 1

Phosphorus Effects:

• Cinacalcet has little or no direct effect on serum phosphorus concentrations, with a mean difference of only -0.07 mmol/L (95% CI, -0.19 to 0.04) 2, 3
• Any phosphorus reduction occurs indirectly through PTH suppression, not by direct phosphate binding 4

Pharmacokinetic Profile

• Cmax is achieved in approximately 2-6 hours after oral administration 1
• Steady-state drug levels are achieved within 7 days of dosing 1
• The drug has a biphasic elimination with an initial half-life of approximately 6 hours and terminal half-life of 30-40 hours 1
• Cinacalcet is extensively distributed (volume of distribution ~1,000 L) and highly protein-bound (93-97%) 1
• Metabolism occurs primarily via CYP3A4, CYP2D6, and CYP1A2, with renal excretion of metabolites being the primary route of elimination (80% urine, 15% feces) 1

Downstream Effects on Bone and Mineral Metabolism

• Reductions in PTH are associated with decreased bone turnover and bone fibrosis in patients with CKD on dialysis and uncontrolled secondary hyperparathyroidism 1
• The drug effectively reduces calcium-phosphorus product levels compared to control treatment 5

Clinical Context and Limitations

Important caveat: While cinacalcet effectively improves surrogate biochemical markers (PTH, calcium), it does not improve mortality or cardiovascular events despite these biochemical improvements, with a relative risk of 0.97 (95% CI, 0.89-1.05) for all-cause mortality 2, 4. This represents a critical disconnect between mechanism of action on biochemical parameters and clinical outcomes that matters most to patients—a pattern previously seen with vitamin D compounds in CKD 2.