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Drug Criteria & Outcomes: Cinacalcet HCl (Sensipar) Formulary Evaluation
Part 1 of 2: Indications, Mechanism of Action, Pharmacokinetics, Dosing & Administration, Adverse Events, amd Interactions
By April H. Eubanks,
Harrison School of Pharmacy
Auburn (AL) University
Cinacalcet is the first in a class of calcimimetic agents that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium.
Cinacalcet is indicated for the treatment of:
Background on indications
Secondary hyperparathyroidism in patients with chronic kidney disease on dialysis:
Renal osteodystrophy, also known as renal bone disease, is a major cause of morbidity and mortality in patients with chronic kidney disease on dialysis. As renal failure progresses and glomerular filtration rate (GFR) declines, the kidneys’ ability to excrete phosphorus also declines, resulting in hyperphosphatemia. About 70% of all patients with end stage-renal disease (ESRD) have hyperphosphatemia, with approximately 40% having values that exceed 6.5 mg/dL (normal: 2.5-4.5 mg/dL).
High levels of phosphorus directly stimulate the release of parathyroid hormone (PTH). In addition, retention of phosphorus inhibits renal activation of vitamin D, which, in turn, reduces gut absorption of calcium. Low levels of calcium in the blood provide a major stimulus for secretion of PTH.
The parathyroid glands secrete PTH in an attempt to restore the normal balance of phosphorus and calcium. In normal patients, PTH release reduces reabsorption of phosphorus in the renal tubule and promotes its excretion. Thus, phosphorus and calcium levels return to normal. However, as functional renal mass declines, this renal response to PTH declines and hyperphosphatemia is not relieved. The resulting hypocalcemia causes PTH to stimulate the release of calcium through mobilization from bone.
Traditional agents used to treat hyperparathyroidism typically include vitamin D sterols and calcium-containing phosphate binders. These agents, however, put the patient at risk for developing hypercalcemia and may not be efficient at resolving the hyperparathyroidism.
Hypercalcemia secondary to parathyroid carcinoma occurs as the result of uncontrolled release of PTH.
Mechanism of action
Cinacalcet prevents progression to renal osteo-dystrophy by decreasing PTH secretion. The calcium-sensing receptor located on the surface of the chief cell of the parathyroid gland is the principle regulator of PTH secretion. Cinacalcet increases the sensitivity of the calcium-sensing receptor to extracellular calcium, and thus, reduces the stimulation of PTH secretion. This reduction of PTH, in turn, reduces mobilization of bone.
Absorption and distribution
Metabolism and excretion
— oxidative N-dealkylation;
— oxidation of the naphthalene ring on the parent drug.
• Renal excretion is the primary route of elimination with approximately 80% of the dose recovered in the urine and 5% in the feces.
Recommended dosing and administration
Secondary hyperparathyroidism in patients with CKD on dialysis
Serum calcium and phosphorus should be measured within one week, and PTH should be measured one to four weeks after initiation or dose adjustment. Once the maintenance dose has been established, serum calcium and phosphorus should be measured about every month, and PTH every one to three months.
The incidence of serious adverse events was similar in the cinacalcet and placebo groups, 29% and 31%, respectively (see Table 1, below).
Cinacalcet is a strong inhibitor of CYP2D6, but not CYP1A2, CYP2C9, CYP2C19, or CYP3A4. Cinacalcet also is a substrate of CYP1A2, CYP2D6, and CYP3A4 (see Table 2, below for more information on interactions).
In addition to these, any inducers or inhibitors of CYP1A2, CYP2D6, or CYP3A4 could potentially affect the metabolism of cinacalcet.
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Store at 25°C (77°F); when outside normal storage conditions, keep drug in temperature range of 15-30°C (59-86°F).