The calcium-sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH synthesis and secretion. Cinacalcet, the active ingredient in cinacalcet tablets, is a calcimimetic agent that directly lowers PTH levels by increasing the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. The reduction in PTH is associated with a concomitant decrease in serum calcium levels.
Reduction in iPTH levels correlated with the plasma cinacalcet concentrations in patients with CKD. The nadir in iPTH level occurs approximately 2 to 6 hours post dose, corresponding with the maximum plasma concentration (C max ) of cinacalcet. After steady-state cinacalcet concentrations are reached (which occurs within 7 days of dose change), serum calcium concentrations remain constant over the dosing interval in patients with CKD.
Reductions in PTH are associated with a decrease in bone turnover and bone fibrosis in patients with CKD on dialysis and uncontrolled secondary HPT.
Absorption and Distribution
After oral administration of cinacalcet, C max is achieved in approximately 2 to 6 hours. Cinacalcet C max and AUC (0-inf inite ) were increased by 82% and 68%, respectively, following administration with a high-fat meal compared with fasting in healthy volunteers. The C max and AUC (0-inf inite ) of cinacalcet were increased by 65% and 50%, respectively, when cinacalcet was administered with a low-fat meal compared with fasting.
After absorption, cinacalcet concentrations decline in a biphasic fashion with an initial half-life of approximately 6 hours and terminal half-life of 30 to 40 hours. Steady-state drug levels are achieved within 7 days, and the mean accumulation ratio is approximately 2 with once daily oral administration. The median accumulation ratio is approximately 2 to 5 with twice daily oral administration. The AUC and C max 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 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 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 forming 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 the parent drug concentrations. The hydrocinnamic acid metabolite and glucuronide conjugates have minimal or no calcimimetic activity. 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.
Age: Geriatric P opulation
The pharmacokinetic profile of cinacalcet in geriatric patients (age ≥ 65 years, n = 12) is similar to that for patients who are < 65 years of age (n = 268) [see Use in Specific Populations ( 8.5)].
The disposition of a 50 mg cinacalcet single dose was compared between patients with hepatic impairment and patients with normal hepatic function. Cinacalcet exposure (AUC (0-inf inite ) ) 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 (AUC (0-inf inite ) ) were 2.4 and 4.2 fold higher, respectively, than that in healthy volunteers. The mean half-life of cinacalcet increased from 49 hours in healthy volunteers to 65 hours and 84 hours in patients with moderate and severe hepatic impairment, respectively. Protein binding of cinacalcet is not affected by impaired hepatic function [see Use in Specific Populations ( 8.7)].
The pharmacokinetic profile of a 75 mg cinacalcet single dose in patients with mild, moderate, and severe renal impairment, and those on hemodialysis or peritoneal dialysis is comparable with that in healthy volunteers [see Use in Specific Populations ( 8.6)].
In vitro studies indicate that cinacalcet is a strong inhibitor of CYP2D6, but not an inhibitor of CYP1A2, CYP2C9, CYP2C19, and CYP3A4. In vitro induction studies indicate that cinacalcet is not an inducer of CYP450 enzymes. Tables 5 and 6 list the findings from in vivo drug-drug interaction studies.
|Co — administered drug and dosing regimen||Cinacalcet|
|Dose *||Mean change in AUC (0-inf)||Mean change in C max|
|200 mg ketoconazole twice daily for 7 days||90 mg on day 5||↑127%||↑116%|
|1500 mg calcium carbonate, single dose||100 mg||↓6%||↓5%|
|80 mg pantoprazole daily for 3 days||90 mg on day 3||↑1%||↓3%|
|2400 mg sevelamer HCl three times a day for 2 days||90 mg on day 1 with first dose of sevelamer||↓4%||↓7%|
|Cinacalcet dosing regimen||Co — administered drug|
|Name and Dose||Mean change in AUC (0-inf)||Mean change in C max|
|30 mg twice daily for 8 days||25 mg warfarin * tablet †||↑1% for R-warfarin ↓1% for S-warfarin||↓10% for R-warfarin ↓12% for S-warfarin|
|90 mg daily for 7 days to CYP2D6 extensive metabolizers||50 mg desipramine †||↑264%||↑75%|
|90 mg daily for 5 days||2 mg midazolam †||↑5%||↓5%|
|25 or 100 mg single dose to CYP2D6 extensive metabolizers||50 mg amitriptyline single dose||↑21-22% for amitriptyline ↑17-23% for nortriptyline ‡||↑13-21% for amitriptyline ↑11-15% for nortriptyline ‡|
*No significant change in prothrombin time.
† Single dose on day 5.
‡ Nortriptyline is an active metabolite of amitriptyline.
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