Cincalcet for the treatment of secondary hyperparathyrodism in end-stage renal disease when on maintenance dialysis therapy

Cinacalcet is a calcimimetic agent which increases the sensitivity of calcium-sensing receptors to extracellular calcium ions, thereby inhibiting the release of PTH

• licensed for the treatment of secondary hyperparathyroidism in patients with ESRD on maintenance dialysis therapy. It may be used as part of a therapeutic regimen including phosphate binders and/or vitamin D sterols, as appropriate
  • dose is titrated to achieve a target level of intact PTH of between 15.9 and 31.8 pmol/litre (150-300 pg/ml)
  • because cinacalcet lowers calcium levels, it is contraindicated if serum calcium is below the lower limit of the normal range
  • most commonly reported adverse effects in clinical trials were nausea and vomiting. These were mild to moderate in nature and transient in most cases
  • for full details of side effects and contraindications, see the summary of product characteristics (SPC).

NICE have stated that:

• cinacalcet is not recommended for the routine treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy
• cinacalcet is recommended for the treatment of refractory secondary hyperparathyroidism in patients with end-stage renal disease (including those with calciphylaxis) only in those:
  • who have 'very uncontrolled' plasma levels of intact parathyroid hormone (defined as greater than 85 pmol/litre (800 pg/ml)) that are refractory to standard therapy, and
  • a normal or high adjusted serum calcium level, and
  • in whom surgical parathyroidectomy is contraindicated, in that the risks of surgery are considered to outweigh the benefits
• response to treatment should be monitored regularly and treatment should be continued only if a reduction in the plasma levels of intact parathyroid hormone of 30% or more is seen within 4 months of treatment, including dose escalation as appropriate.

Notes:

• development of secondary hyperparathyroidism in people with impaired renal function is complex
  • occurs as a result of failure of the excretory function of the kidney (impaired excretion of phosphate and impaired reabsorption of calcium) and of the endocrine function of the kidney (reduced hydroxylation of inactive forms of vitamin D to the active form, calcitriol [1,25-dihydroxyvitamin D])
    • in the early stages of renal impairment, phosphate excretion is reduced. Initially, this does not lead to high levels of phosphate in the blood (hyperphosphataemia) because increased secretion of PTH stimulates the kidneys to excrete more phosphate
    • when renal impairment progresses to the moderate stage, the kidneys can no longer eliminate more phosphate in response to increased PTH secretion, and phosphate levels begin to rise
      • hyperphosphataemia suppresses the renal hydroxylation of inactive calcidiol (25hydroxyvitamin D) to calcitriol
      • low levels of calcitriol lead to reduced intestinal absorption of calcium, leading in turn to hypocalcaemia
      • hypocalcaemia, low calcitriol levels and hyperphosphataemia all independently stimulate PTH synthesis and secretion
      • as these chronic stimuli persist, the parathyroid glands become enlarged and begin to function autonomously, continuing to secrete PTH even if hypocalcaemia is corrected. This condition is referred to as 'refractory' hyperparathyroidism and is also sometimes called 'tertiary' hyperparathyroidism
        • PTH levels become extremely elevated and this causes calcium and phosphate to be released from bone. Hyperphosphataemia is exacerbated and hypercalcaemia may occur.

Reference:

• 1) NICE (January 2007). Cinacalcet for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy