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Sensipar

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Sensipar

CLINICAL PHARMACOLOGY

Mechanism Of Action

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 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.

Pharmacodynamics

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 (Cmax) 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.

Pharmacokinetics

Absorption and Distribution

After oral administration of cinacalcet, Cmax is achieved in approximately 2 to 6 hours. Cinacalcet Cmax and AUC(0-infinite) were increased by 82% and 68%, respectively, following administration with a high-fat meal compared with fasting in healthy volunteers. The Cmax and AUC(0-infinite) 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 a 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 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 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.

Specific Populations
Age: Geriatric Population

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].

Age: Pediatric Population

The pharmacokinetics of cinacalcet has not been studied in patients < 18 years of age [see Use in Specific Populations].

Hepatic Impairment

The disposition of a 50 mg Sensipar single dose was compared between patients with hepatic impairment and patients with normal hepatic function. Cinacalcet exposure (AUC(0-infinite)) 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-infinite)) 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 WARNINGS AND PRECAUTIONS and Use in Specific Populations].

Renal Impairment

The pharmacokinetic profile of a 75 mg Sensipar 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].

Drug Interactions

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.

Table 5: Effect of co-administered drugs on cinacalcet

Co-administered drug and dosing regimen Cinacalcet
Dose* Mean change in AUC (0-inf) Mean change in Cmax
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%
*Single dose.

Table 6: Effect of cinacalcet co-administration on other drugs

Cinacalcet dosing regimen Co-administered drug
Name and Dose Mean change in AUC(0-inf) Mean change in Cmax
30 mg twice daily for 8 days 25 mg warfarin* tablet† ↑1 % for R-warfarin
↓1% 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.

Clinical Studies

Secondary Hyperparathyroidism In Patients With Chronic Kidney Disease On Dialysis

Three 6-month, multicenter, randomized, double-blind, placebo-controlled clinical studies of similar design were conducted in patients with CKD on dialysis. A total of 665 patients were randomized to Sensipar and 471 patients to placebo. The mean age of the patients was 54 years, 62% were male, and 52% were Caucasian. The average baseline iPTH level by the Nichols IRMA was 712 pg/mL, with 26% of the patients having a baseline iPTH level > 800 pg/mL. The mean baseline Ca x P product was 61 mg2/dL2 . The average duration of dialysis prior to study enrollment was 67 months. Ninety-six percent of patients were on hemodialysis and 4% on peritoneal dialysis. At study entry, 66% of the patients were receiving vitamin D sterols and 93% were receiving phosphate binders. Sensipar (or placebo) was initiated at a dose of 30 mg once daily and titrated every 3 or 4 weeks to a maximum dose of 180 mg once daily to achieve an iPTH of < 250 pg/mL. The dose was not increased if a patient had any of the following: iPTH < 200 pg/mL, serum calcium < 7.8 mg/dL, or any symptoms of hypocalcemia. If a patient experienced symptoms of hypocalcemia or had a serum calcium < 8.4 mg/dL, calcium supplements and/or calcium-based phosphate binders could be increased. If these measures were insufficient, the vitamin D dose could be increased. Approximately 70% of patients in the Sensipar arm and 80% of the patients in the placebo arm completed the 6-month studies. In the primary efficacy analysis, 40% of the patients on Sensipar and 5% of placebo-treated patients achieved an iPTH < 250 pg/mL (p < 0.001) (Table 7, Figure 1). These studies showed that Sensipar reduced iPTH while lowering Ca x P, calcium, and phosphorus levels (Table 7, Figure 2). The median dose of Sensipar at the completion of the studies was 90 mg. Patients with milder disease typically required lower doses.

Similar results were observed when either the iPTH or biointact PTH (biPTH) assay was used to measure PTH levels in CKD patients on dialysis; treatment with cinacalcet did not alter the relationship between iPTH and biPTH.

Table 7: Effects of Sensipar on iPTH, Ca x P, Serum Calcium, and Serum Phosphorus in 6-month Phase 3 Studies (Patients on Dialysis)

  Study 1 Study 2 Study 3
Placebo
(n = 205)
Sensipar
(n = 205)
Placebo
(n = 165)
Sensipar
(n = 166)
Placebo
(n = 101)
Sensipar
(n = 294)
iPTH
  Baseline (pg/mL): Median 535 537 556 547 670 703
  Mean (SD) 651 (398) 636 (341) 630 (317) 652 (372) 832 (486) 848 (685)
  Evaluation Phase (pg/mL) 563 275 592 238 737 339
  Median Percent Change +3.8 -48.3 +8.4 -54.1 +2.3 -48.2
  Patients Achieving Primary Endpoint (iPTH ≤ 250 pg/mL) (%)a 4% 41%** 7% 46%** 6% 35%**
  Patients Achieving ≥ 30% Reduction in iPTH (%)a 11% 61% 12% 68% 10% 59%
  Patients Achieving iPTH ≤ 250 pg/mL and Ca x P ≤ 55 mg2/dL2 (%) 1% 32% 5% 35% 5% 28%
Ca x P
  Baseline (mg2/dL2) 62 61 61 61 61 59
  Evaluation Phase (mg2/dL2) 59 52 59 47 57 48
  Median Percent Change -2.0 -14.9 -3.1 -19.7 -4.8 -15.7
Calcium
  Baseline (mg/dL) 9.8 9.8 9.9 10.0 9.9 9.8
  Evaluation Phase (mg/dL) 9.9 9.1 9.9 9.1 10.0 9.1
  Median Percent Change +0.5 -5.5 +0.1 -7.4 +0.3 -6.0
Phosphorus
  Baseline (mg/dL) 6.3 6.1 6.1 6.0 6.1 6.0
  Evaluation Phase (mg/dL) 6.0 5.6 5.9 5.1 5.6 5.3
  Median Percent Change -1.0 -9.0 -2.4 -12.4 -5.6 -8.6
** p < 0.001 compared with placebo; p-values presented for primary endpoint only.
aiPTH value based on averaging over the evaluation phase (defined as weeks 13 to 26 in studies 1 and 2 and weeks 17 to 26 in study 3). Values shown are medians unless indicated otherwise.

Figure 1: Mean (SE) iPTH Values (Pooled Phase 3 Studies)

Mean (SE) iPTH Values - Illustration

Data are presented for patients who completed the studies; Placebo (n = 342), Sensipar (n = 439).

Figure 2: Mean (SE) Ca x P Values (Pooled Phase 3 Studies)

Mean (SE) Ca x P Values - Illustration

Data are presented for patients who completed the studies; Placebo (n = 342), Sensipar (n = 439).

Reductions in iPTH and Ca x P were maintained for up to 12 months of treatment.

Sensipar decreased iPTH and Ca x P levels regardless of disease severity (i.e., baseline iPTH value), duration of dialysis, and whether or not vitamin D sterols were administered. Approximately 60% of patients with mild (iPTH ≥ 300 to < 500 pg/mL), 41% with moderate (iPTH > 500 to 800 pg/mL), and 11% with severe (iPTH > 800 pg/mL) secondary HPT achieved a mean iPTH value of < 250 pg/mL. Plasma iPTH levels were measured using the Nichols IRMA.

Parathyroid Carcinoma

Twenty-nine patients with Parathyroid Carcinoma were enrolled in a single-arm, open-label study. The study consisted of two phases, a dose-titration phase and a maintenance phase. Patients initially received 30 mg cinacalcet twice daily and then were titrated every 2 weeks to a maximum dose of 90 mg four times daily. Dosage escalation during the variable-length (2 to 16 weeks) titration phase continued until the serum calcium concentration was < 10 mg/dL (2.5 mmol/L), the patient reached the highest possible dosage, or adverse events precluded further dosage increases.

Twenty-nine patients entered the study. The median exposure to cinacalcet was 229 days (range: 1 to 1051). At baseline the mean (SE) serum calcium was 14.1 (0.4) mg/dL. At the end of the titration phase, the mean (SE) serum calcium was 12.4 (0.5) mg/dL, which is a mean reduction of 1.7 (0.6) mg/dL from baseline. Figure 3 illustrates mean serum calcium (mg/dL) over time for all patients still on study at each time point from the beginning of titration to study visit week 80. Daily dose during the study ranged from 30 mg twice daily to 90 mg four times daily.

Figure 3: Serum Calcium Values in Patients With Parathyroid Carcinoma Receiving Sensipar at Baseline, Titration, and Maintenance Phase

Serum Calcium Values in Patients With Parathyroid Carcinoma Receiving Sensipar at Baseline, Titration, and Maintenance Phase - Illustration

n = Number of patients with non-missing values at the timepoint. End of Titration (EOT) phase could occur at any visit from week 2 to 16. Patients at EOT are those who completed titration.

Patients With Hypercalcemia Due To Primary Hyperparathyroidism

Seventeen patients with severe hypercalcemia due to primary HPT, who had failed or had contraindications to parathyroidectomy, participated in an open-label, single-arm study. The study consisted of two phases, a dose-titration phase and a maintenance phase. In this trial, severe hypercalcemia was defined as a screening serum calcium level of > 12.5 mg/dL. Patients initially received 30 mg cinacalcet twice daily and then were titrated every 2 weeks to a maximum dose of 90 mg 4 times daily. Dosage escalation during the variable-length (2 to 16 weeks) titration phase continued until the serum calcium concentration was < 10 mg/dL (2.5 mmol/L), the patient reached the highest possible dosage, or adverse events precluded further dosage increases.

Seventeen patients entered the study. The median exposure to cinacalcet was 270 days (range: 32 to 1,105). At baseline the mean (SE) serum calcium was 12.7 (0.2) mg/dL. At the end of the titration phase the mean (SE) serum calcium was 10.4 (0.3) mg/dL, which is a mean reduction of 2.3 (0.3) mg/dL from baseline. Figure 4 illustrates mean serum calcium (mg/dL) over time for all patients still on study at each time point from the beginning of titration to study visit week 80. Daily dose during the study ranged from 30 mg twice a day to 90 mg four times a day.

Figure 4: Mean Serum Calcium (SE) at Baseline, End of Titration, and Scheduled Maintenance Visits (Patients with Severe intractable primary HPT)

Mean Serum Calcium (SE) at Baseline, End of Titration, and Scheduled Maintenance Visits - Illustration

n = Number of patients with non-missing values at the timepoint. End of Titration (EOT) phase could occur at any visit from week 2 to 16. Patients at EOT are those who completed titration.

Sixty-seven patients with primary HPT who met criteria for parathyroidectomy on the basis of corrected total serum calcium ( > 11.3 mg/dl [2.82 mmol/L] and < 12.5 mg/dl [3.12 mmol/L]), but who were unable to undergo parathyroidectomy participated in a randomized, double-blind, placebo-controlled study. A total of 33 patients were randomized to Sensipar and 34 patients randomized to placebo. The mean age of the patients was 72 years, 52% were female, 61% were Caucasian, and 5% were Blacks. The study started with a 12-week titration phase, followed by a 16-week efficacy assessment phase. Cinacalcet was initiated at a dose of 30 mg twice daily and titrated to maintain a corrected total serum calcium concentration within the normal range. During the efficacy period a significantly higher percentage of cinacalcet treated patients compared with the placebo treated patients achieved mean corrected total serum calcium concentration ( ≤ 10.3 mg/dL [2.57 mmol/L], 75.8% vs 0%, p < 0.001) and ≥ 1 mg/dL [0.25 mmol/L] decrease from baseline in mean corrected total serum calcium concentration (84.8% vs 5.9%, p < 0.001). The median dose of Sensipar at the completion of the study was 60 mg/day.

Last reviewed on RxList: 12/11/2014
This monograph has been modified to include the generic and brand name in many instances.

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