DESCRIPTION
Sensipar® (cinacalcet hydrochloride) is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. Its empirical formula is C22H22F3N•HCl with a molecular weight of 393.9 g/mol (hydrochloride salt) and 357.4 g/mol (free base). It has one chiral center having an R-absolute configuration. The Renantiomer is the more potent enantiomer and has been shown to be responsible for pharmacodynamic activity.
Cinacalcet HCl is a white to off-white, crystalline solid that is soluble in methanol or 95% ethanol and slightly soluble in water.
Sensipar® tablets are formulated as light-green, film-coated, oval-shaped tablets for oral administration in strengths of 30 mg, 60 mg, and 90 mg of cinacalcet HCl as the free base equivalent (33 mg, 66 mg, and 99 mg as the hydrochloride salt, respectively).
Cinacalcet HCl is described chemically as N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane hydrochloride and has the following structural formula:
Inactive Ingredients: Sensipar® tablets are comprised of the active ingredient, and the following inactive ingredients: pre-gelatinized starch, microcrystalline cellulose, povidone, crospovidone, colloidal silicon dioxide, and magnesium stearate. Tablets are coated with color (Opadry®II green) and clear film-coat (Opadry® clear), carnauba wax, and Opacode® black ink.
CLINICAL PHARMACOLOGY
Mechanism of Action
Secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) is a progressive disease, associated with increases in parathyroid hormone (PTH) levels and derangements in calcium and phosphorus metabolism. Increased PTH stimulates osteoclastic activity resulting in cortical bone resorption and marrow fibrosis. The goals of treatment of secondary hyperparathyroidism are to lower levels of PTH, calcium, and phosphorus in the blood, in order to prevent progressive bone disease and the systemic consequences of disordered mineral metabolism. In CKD patients on dialysis with uncontrolled secondary HPT, reductions in PTH are associated with a favorable impact on bone-specific alkaline phosphatase (BALP), bone turnover and bone fibrosis.
The calcium-sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH secretion. Sensipar® directly lowers PTH levels by increasing the sensitivity of the calcium-sensing receptor to extracellular calcium. The reduction in PTH is associated with a concomitant decrease in serum calcium levels.
Pharmacokinetics
Absorption and Distribution:
After oral administration of cinacalcet, maximum plasma concentration (Cmax) is achieved in approximately 2 to 6 hours. A food-effect study in healthy volunteers indicated that the Cmax and area under the curve (AUC(0-inf)) were increased 82% and 68%, respectively, when cinacalcet was administered with a high-fat meal compared to fasting. Cmax and AUC(0-inf) of cinacalcet were increased 65% and 50%, respectively, when cinacalcet was administered with a low-fat meal compared to fasting.
After absorption, cinacalcet concentrations decline in a biphasic fashion with a terminal half-life of 30 to 40 hours. Steady-state drug levels are achieved within 7 days. The mean accumulation ratio is approximately 2 with once-daily oral administration. The median accumulation ra
