tio is approximately 2 to 5 with twice-daily oral administration. The AUC and Cmax of cinacalcet increase proportionally over the dose range of 30 to 180 mg once daily. The pharmacokinetic profile of cinacalcet does not change over time with once-daily dosing of 30 to 180 mg. The volume of distribution is high (approximately 1000 L), indicating extensive distribution. Cinacalcet is approximately 93 to 97% bound to plasma protein(s). The ratio of blood cinacalcet concentration to plasma cinacalcet concentration is 0.80 at a blood cinacalcet concentration of 10 ng/mL.
Metabolism and Excretion:
Cinacalcet is metabolized 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 β-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. The plasma concentrations of the major circulating metabolites including the cinnamic acid derivatives and glucuronidated dihydrodiols markedly exceed parent drug concentrations. The hydrocinnamic acid metabolite was shown to be inactive at concentrations up to 10 µM in a cell-based assay measuring calcium-receptor activation. The glucuronide conjugates formed after cinacalcet oxidation were shown to have a potency approximately 0.003 times that of cinacalcet in a cell-based assay measuring a calcimimetic response. Renal excretion of metabolites was the primary route of elimination of radioactivity. Approximately 80% of the dose was recovered in the urine and 15% in the feces.
Special Populations
Hepatic Insufficiency:
The disposition of a 50 mg cinacalcet single dose was compared in patients with hepatic impairment and subjects with normal hepatic function. Cinacalcet exposure, AUC(0-inf), was comparable between healthy volunteers and patients with mild hepatic impairment. However, in patients with moderate and severe hepatic impairment (as indicated by the Child-Pugh method), cinacalcet exposures as defined by the AUC(0-inf) were 2.4 and 4.2 times higher, respectively, than that in normals. The mean half-life of cinacalcet is prolonged by 33% and 70% in patients with moderate and severe hepatic impairment, respectively. Protein binding of cinacalcet is not affected by impaired hepatic function. See PRECAUTIONS and DOSAGE AND ADMINISTRATION.
Renal Insufficiency:
The pharmacokinetic profile of a 75 mg Sensipar® single dose in patients with mild, moderate, and severe renal insufficiency, and those on hemodialysis or peritoneal dialysis is comparable to that in healthy volunteers.
Geriatric Patients:
The pharmacokinetic profile of Sensipar® in geriatric patients (age ≥ 65, n = 12) is similar to that for patients who are < 65 years of age (n = 268).
Pediatric Patients:
The pharmacokinetics of Sensipar® have not been studied in patients < 18 years of age.
Drug Interactions
An in vitro study indicates that cinacalcet is a strong inhibitor of CYP2D6, but not of CYP1A2, CYP2C9, CYP2C19, and CYP3A4.
Ketoconazole: Cinacalcet AUC(0-inf) and Cmax increased 2.3 and 2.2 times, respectively, when a sing |
