CaR/Ca receptor

AMG-073 orally administered to normal rats at doses of 1, 3, 10, and 30 mg/kg in 20% sulfobutyl ether β-cyclodextrin sodium causes a notable dose-dependent decrease in PTH levels that lasts for one to four hours. The 10- and 30-mg/kg doses of AMG-073 cause notable drops in PTH levels at 8 hours when compared to controls; these reductions disappear after 24 hours. After oral administration of AMG-073, 10, 30, and 40 mg/kg, respectively, there is a significant dose-dependent reduction in serum calcium levels at 4, 8, and 24 hours later. Only at the maximum dose of AMG-073 is a temporary drop in serum phosphorus levels seen. Furthermore, rats given 40 mg/kg of AMG-073 showed elevated calcitonin levels that correlated with PTH suppression. After oral administration of AMG-073, PTH and calcium levels rapidly decrease in five out of six nephrectomized rats, as they do in normal rats. Moreover, parathyroid weight is significantly decreased by oral AMG-073 at 5 and 10 mg/kg for 4 weeks when compared to controls.

---

Administration of Cinacalcet HCl (5 or 10 mg/kg) significantly reduced the number of PCNA-positive cells and decreased parathyroid weight compared with vehicle-treated 5/6 nephrectomized rats. There was no difference in apoptosis from cinacalcet HCl-treated or vehicle-treated animals. Serum PTH and blood ionized calcium levels decreased in cinacalcet HCl-treated animals compared with vehicle-treated controls. Conclusion: The results confirm previous work demonstrating that calcimimetic agents attenuate the progression of parathyroid hyperplasia in subtotally nephrectomized rats, extending earlier observations to now include cinacalcet HCl. These results support a role for the CaR in regulating parathyroid cell proliferation. Therefore, cinacalcet HCl may represent a novel therapy for improving the management of secondary HPT [1].

---

Calcimimetics, such as cinacalcet (Cin), increase the sensitivity of the CaR to Ca. The effects of Cin on UCa are complex and difficult to predict. We tested the hypothesis that Cin would alter urinary (U) Ca and supersaturation with respect to calcium hydrogen phosphate (CaHPO(4)) and calcium oxalate (CaOx). GHS or control rats were fed a normal Ca diet (0.6% Ca) for 28 days with Cin (30 mg/kg/24 h) added to the diet of half of each group for the last 14 days. The protocol was then repeated while the rats were fed a low Ca (0.02% Ca) diet. We found that Cin led to a marked reduction in circulating parathyroid hormone and a modest reduction in serum Ca. Cin did not alter UCa when the GHS rats were fed the normal Ca diet but lowered UCa when they were fed the low Ca diet. However, Cin did not alter U supersaturation with respect to either CaOx or CaHPO(4) on either diet. If these findings in GHS rats can be confirmed in man, it suggests that Cin would not be an effective agent in the treatment of human idiopathic hypercalciuria and resultant stone formation [2].

The compounds were evaluated in CHO cells transfected with the hCaSR and a 6×TRE luciferase reporter system.12 Compounds were tested in dose response, with increasing calcium concentration. The increasing concentration of a positive allosteric modulator induces a dose proportional leftward shift of the hCaSR calcium responses. The values indicated in this paper correspond to an EC50 at 2 mM of calcium. The most active compounds were then tested in vivo for their ability to decrease PTH levels in normal rats. Our two starting points, R-568 and Fendiline, were active at 80 and 1000 nM, respectively, and led to compound 46, active at 60 nM. Cinacalcet was found at 80 nM in this assay.[PMID: 23465611] https://pubmed.ncbi.nlm.nih.gov/23465611/

The Apoptag System measures nuclear DNA fragmentation in situ to identify apoptosis in parathyroid glands from 5/6 nephrectomized or sham rats treated with Cinacalcet HCl (10 mg/kg) or vehicle. In summary, after being treated with vehicle or cinacalcet HCl, parathyroid gland sections from the animals are digested using 20 μg/mL proteinase K in 0.1 mol/L PBS at room temperature for 15 minutes.To block endogenous peroxidase, the samples are then incubated with 3% hydrogen peroxide/methanol for 5 minutes. To label exposed 3′-OH DNA ends with digoxigenin-tagged nucleotides, sections are incubated with terminal deoxynucleotidyl transferase (TdT) for 1 hour at 37°C. The immunoperoxidase method finds DNA that has been labeled with digoxigenin. The nuclei of apoptotic cells are stained brown, and sections are created using 3,3′-diaminobenzidine (DAB). When TdT is replaced with distilled water, the specificity for apoptosis is confirmed using negative staining.

---

Cinacalcet HCl dosing for 4 weeks [1]
Starting 6 weeks postsurgery, 5/6 nephrectomized (N = 35) and sham (N = 18) animals received orally either vehicle (20% captisol in water) (mL/kg) or Cinacalcet HCl (1, 5, or 10 mg/kg) for 4 weeks. Sampling for the determination of serum PTH and serum chemistries after the initiation of cinacalcet HCl treatment began at the 8-week time point (see Figures 4 and 5 ).

---

Apoptosis [2]
To identify apoptosis in parathyroid glands from 5/6 nephrectomized or sham rats treated with vehicle [phosphate-buffered saline (PBS)] or Cinacalcet HCl (10 mg/kg), nuclear DNA fragmentation was measured in situ using the Apoptag System. Briefly, parathyroid gland sections from animals treated with vehicle or cinacalcet HCl were digested with 20 μg/mL proteinase K in 0.1 mol/L PBS at room temperature for 15 minutes and incubated with 3% hydrogen peroxide/methanol for 5 minutes to block endogenous peroxidase. Sections were incubated for 1 hour at 37°C with terminal deoxynucleotidyl transferase (TdT) to label exposed 3′-OH DNA ends with digoxigenin-tagged nucleotides. Digoxigenin-labeled DNA was detected by the immunoperoxidase method. Sections were developed with 3,3′-diaminobenzidine (DAB), and the nuclei of apoptotic cells were stained brown. The specificity for apoptosis was verified by negative staining when distilled water was substituted for TdT.
Fourteen 67th generation female GHS rats and 14 female Sprague–Dawley Ctl rats, initially weighing on average 238 g, were placed in metabolic cages. From days 1 to 14, each rat in each group was fed 13 g/day of a NCD (0.6% Ca and 0.65% P, Harlan Teklad, Madison, WI, USA). We have previously shown that rats of this size completely consume this amount of diet on a daily basis.15, 17, 18, 19, 20 During the last 5 days of this period (day 10–14), five successive 24-h urine collections were obtained. Three (first, second, fourth) were collected in concentrated HCl (0.5 ml) for all measurements except for pH, uric acid, and chloride and two collections (third and fifth) were collected in the presence of thymol for measurement of pH, uric acid, and chloride. All samples were refrigerated at 4°C until measurement and all measurements were completed within 2 weeks.
From days 15 to 28, half of each group (seven GHS and seven Ctl rats), chosen at random, was continued on NCD without modification and the other half (seven GHS and seven Ctl rats) was fed NCD supplemented with Cinacalcet (30 mg/kg/day) (Amgen Inc., Thousand Oaks, CA, USA). This dose has been shown to significantly inhibit PTH in normal rats.36 In humans, the terminal half-life of Cinacalcet is 30–40 h and steady-state drug levels are reached in 7 days.36, 37 During the last 5 days of this period (day 24–28), five successive 24-h urine collections were obtained as during days 10–14.
From days 29 to 42, all GHS and Ctl rats were fed 13 g/day of a LCD (0.02% Ca and 0.65% P). No rat received Cinacalcet. LCD was utilized to remove the contribution of appreciable intestinal Ca absorption to UCa excretion. During the last 5 days of this period (day 38–42), five successive 24-h urine collections were obtained as during days 10–14. From days 43 to 56, half of each group (seven GHS and seven Ctl rats) was continued on LCD without modification and the other half (the same seven GHS and seven Ctl rats that had previously received Cinacalcet) was fed LCD supplemented with Cinacalcet (30 mg/kg/day). During the last 5 days of this period (day 52–56), five successive 24-h urine collections were obtained as during days 10–14.

Absorption, Distribution and Excretion
Rapidly absorbed following oral administration.
Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4, CYP2D6 and CYP1A2. Renal excretion of metabolites was the primary route of elimination of radioactivity.
1000 L
The metabolism and disposition of calcimimetic agent cinacalcet HCl was examined after a single oral administration to mice, rats, monkeys, and human volunteers. In all species examined, cinacalcet was well absorbed, with greater than 74% oral bioavailability of cinacalcet-derived radioactivity in monkeys and humans. In rats, cinacalcet-derived radioactivity was widely distributed into most tissues, with no marked gender-related differences. In all animal models examined, radioactivity was excreted rapidly via both hepatobiliary and urinary routes. In humans, radioactivity was cleared primarily via the urinary route (80%), with 17% excreted in the feces. Cinacalcet was not detected in the urine in humans. ...
After absorption, cinacalcet concentrations decline in a biphasic fashion with a terminal half life of 30 to 40 hours. 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.
Steady-state drug levels are achieved within 7 days. 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 high (approximately 1000 L), indicating extensive distribution. Cinacalcet is approximately 93% to 97% bound to plasma proteins. The ratio of blood cinacalcet concentration to plasma cinacalcet concentration is 0.8 at a blood cinacalcet concentration of 10 ng/mL.
After oral administration of cinacalcet, Cmax is achieved in approximately 2 to 6 hours. A food-effect study in healthy volunteers indicated that the Cmax and AUC were increased 82% and 68%, respectively, when cinacalcet was administered with a high-fat meal compared with fasting, Cmax and AUC of cinacalcet were increased 65% and 50%, respectively, when cinacalcet was administered with a low-fat meal compared with fasting.
For more Absorption, Distribution and Excretion (Complete) data for CINACALCET (6 total), please visit the HSDB record page.

---

Metabolism / Metabolites
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.
The metabolism and disposition of calcimimetic agent cinacalcet HCl was examined after a single oral administration to mice, rats, monkeys, and human volunteers. ... The primary routes of metabolism of cinacalcet were N-dealkylation leading to carboxylic acid derivatives (excreted in urine as glycine conjugates) and oxidation of naphthalene ring to form dihydrodiols (excreted in urine and bile as glucuronide conjugates). The plasma radioactivity in both animals and humans was primarily composed of carboxylic acid metabolites and dihydrodiol glucuronides, with <1% circulating radioactivity accounting for the unchanged cinacalcet. Overall, the circulating and excreted metabolite profile of cinacalcet in humans was qualitatively similar to that observed in preclinical animal models.
Cinacalcet is metabolized by multiple cytochrome P-450 (CYP) isoenzymes, mainly CYP3A4, CYP2D6, and CYP1A2, and is a potent inhibitor of CYP2D6 in vitro.
Rapidly and extensively metabolized hepatically by multiple enzymes, primarily CYP3A4, CYP2D6, and CYP1A2 via oxidative N-dealkylation to hydrocinnamic acid and hydroxy-hydrocinnamic acid which are further metabolized via beta-oxidation and glycine conjugations; the oxidative N-dealkylation process also generates metabolites that contains the naphthalene ring; and oxidation of the naphthalene ring on the parent drug to form dihydrodiols which are further conjugated with glucuronic aicd. The hydrocinnamic acid metabolite was shown to be inactive at concentrations up to 10 uM in a cell-based assay measuring calcium-receptor activation. The glucuronide conjugates formed after oxidation were shown to have a potency approximately 0.003 times that of cinacalcet in a cell-based assay measuring a calcimimetic response.

---

Biological 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.
The mean half life of cinacalcet is prolonged by 33% and 70% in patients with moderate and severe hepatic impairment, respectively.
terminal half-life: 30 to 40 hours

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on cinacalcet during breastfeeding. However, several newborn infants with disorders of calcium metabolism have been safely treated with cinacalcet. Cinacalcet levels in milk are unlikely to be as high as the doses used in these case. If cinacalcet is required by the mother, it is not a reason to discontinue breastfeeding. Until more data are available, cinacalcet should only be used with careful infant monitoring during breastfeeding.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

---

Protein Binding
Approximately 93 to 97% bound to plasma proteins.

---

Interactions
Potential pharmacokinetic interaction (increased plasma concentrations of drugs metabolized principally by cytochrome P450 (CYP) isoenzyme 2D6). In patients receiving cinacalcet 25 or 100 mg concurrently with amitriptyline hydrochloride 50 mg, exposure to amitriptyline and its active metabolite, norrtiptyline, was increased by 20%. Dosage adjustment maybe required if cinacalcet is administered concomitantly with ta drug that has a narrow therapeutic index and is metabolized principally by CYP2D6 (e.g., flecainide, vinblastine, thioridazine, most tricyclic antidepressants).
Potential pharmacokinetic interaction (increased plasma cinacalcet concentrations) with potent CYP3A4 inhibitors (e.g. ketoconazole, erythromycin, itraconazole). Approximate 2.3-fold increase in cinacalcet exposure reported following concomitant administration of a single 90-mg dose of cinacalcet with ketoconazole (200 mg twice daily for 7 days). Cinacalcet dosage adjustment may be required and PTH and serum calcium concentrations should be closely monitored if a potent CYP3A4 inhibitor is initiated or discontinued.

[1]. Cinacalcet HCl attenuates parathyroid hyperplasia in a rat model of secondary hyperparathyroidism. Kidney Int. 2005 Feb;67(2):467-76.

[2]. Effect of cinacalcet on urine calcium excretion and supersaturation in genetic hypercalciuric stone-forming rats. Kidney Int. 2006 May;69(9):1586-92.

Therapeutic Uses
Cinacalcet is indicated for the treatment of hypercalcemia in patients with parathyroid carcinoma. /Included in US product labeling/
Cinacalcet is indicated for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. /Included in US product labeling/
Cinacalcet is used for the treatment of secondary hyperparathyroidism associated with chronic renal disease in patients who are undergoing hemodialysis or peritoneal dialysis; safety and efficacy in patients who are not undergoing dialysis have not been established. Cinacalcet may be used alone or in conjunction with vitamin D analogs and/or phosphate binders.

---

Drug Warnings
In 3 clinical studies of chronic kidney disease (CKD) patients on dialysis, 5% of the patients in the cinacalcet and placebo groups reported a history of seizure disorder at baseline. During the trials, seizures (primarily generalized or tonic-clonic) were observed in 1.4% of cinacalcet-treated patients and 0.4% of placebo-treated patients. Five of the 9 cinacalcet-treated patients had a history of seizure disorder and 2 were receiving antiseizure medication at the time of their seizure. Both placebo-treated patients had a history of seizure disorder and were receiving antiseizure medication at the time of their seizure. While the basis for the reported difference in seizure rate is not clear, the threshold for seizures is lowered by significant reductions in serum calcium levels. Therefore, closely monitor serum calcium levels in patients receiving cinacalcet, particularly in patients with a history of a seizure disorder.
Studies in rats have shown that cinacalcet is excreted in the milk with a high milk-to-plasma ratio. It is not known whether this drug is excreted in human milk. Considering these data in rats and because many drugs are excreted in human milk and there is potential for clinically significant adverse reactions in infants, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the lactating woman.
FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./
Cinacalcet decreases serum calcium concentrations, and therefore patients should be carefully monitored for the occurrence of hypocalcemia. Cinacalcet should not be initiated if the serum calcium concentration is below the lower limit of normal (8.4 mg/dL).
For more Drug Warnings (Complete) data for CINACALCET (10 total), please visit the HSDB record page.

---

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.

C22H22F3N

357.41

357.17

C, 73.93; H, 6.20; F, 15.95; N, 3.92

226256-56-0

Cinacalcet hydrochloride; 364782-34-3; Cinacalcet-d3 hydrochloride; Cinacalcet-d3; 848608-66-2 [Cinacalcet (m2a-glu)]

156419

White to off-white solid powder

1.2±0.1 g/cm3

440.9±45.0 °C at 760 mmHg

220.5±28.7 °C

0.0±1.1 mmHg at 25°C

1.563

5.74

1

4

6

26

422

1

C[C@H](C1=CC=CC2=CC=CC=C21)NCCCC3=CC(=CC=C3)C(F)(F)F

VDHAWDNDOKGFTD-MRXNPFEDSA-N

InChI=1S/C22H22F3N/c1-16(20-13-5-10-18-9-2-3-12-21(18)20)26-14-6-8-17-7-4-11-19(15-17)22(23,24)25/h2-5,7,9-13,15-16,26H,6,8,14H2,1H3/t16-/m1/s1

N-[(1R)-1-naphthalen-1-ylethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.75 mg/mL (7.69 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.75 mg/mL (7.69 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

View More

Solubility in Formulation 3: ≥ 2.75 mg/mL (7.69 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

Solubility in Formulation 4: 30% PEG400+0.5% Tween80+5% Propylene glycol : 30mg/mL

---

 (Please use freshly prepared in vivo formulations for optimal results.)