| Indication |
For the treatment of secondary hyperparathyroidism in patients
with Chronic Kidney Disease who are on hemodialysis or peritoneal
dialysis. Also for the treatment of hypercalcemia in patients with
parathyroid carcinoma. |
| Pharmacodynamics |
Cinacalcet is a drug that acts as a calcimimetic (i.e. it mimics
the action of calcium on tissues). 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. Cinacalcet reduces calcium
levels by increasing the sensitivity of the calcium sensing receptor to
extracellular calcium. |
| Mechanism of action |
The calcium-sensing receptors on the surface of the chief cell of
the parathyroid gland is the principal regulator of parathyroid hormone
secretion (PTH). Cinacalcet directly lowers parathyroid hormone levels
by increasing the sensitivity of the calcium sensing receptors to
activation by extracellular calcium, resulting in the inhibition of PTH
secretion. The reduction in PTH is associated with a concomitant
decrease in serum calcium levels. |
| Absorption |
Rapidly absorbed following oral administration. |
| Volume of distribution |
|
| Protein binding |
Approximately 93 to 97% bound to plasma proteins. |
| Metabolism |
Metabolism is hepatic by multiple enzymes, primarily CYP3A4,
CYP2D6, and CYP1A2. After administration of a 75 mg radiolabeled dose to
healthy volunteers, cinacalcet was rapidly and extensively metabolized
via: 1) oxidative N-dealkylation to hydrocinnamic acid and
hydroxy-hydrocinnamic acid, which are further metabolized via
ß-oxidation and glycine conjugation; the oxidative N-dealkylation
process also generates metabolites that contain the naphthalene ring;
and 2) oxidation of the naphthalene ring on the parent drug to form
dihydrodiols, which are further conjugated with glucuronic acid. |
| Route of elimination |
Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4,
CYP2D6 and CYP1A2. Renal excretion of metabolites was the primary route
of elimination of radioactivity. |
| Half life |
Terminal half-life is 30 to 40 hours. The mean half-life of
cinacalcet is prolonged by 33% and 70% in patients with moderate and
severe hepatic impairment, respectively. |
| Clearance |
Not Available |
| Toxicity |
Doses titrated up to 300 mg once daily have been safely
administered to patients on dialysis. Overdosage of cinacalcet may lead
to hypocalcemia. |
