CaSR ( EC50 = 2.8 μM )

In vitro activity: AMG-073 belongs to a novel class of drugs called calcimimetics that are used to treat hyperparathyroidism. These drugs decrease the production and secretion of parathyroid hormone (PTH) by making the parathyroid calcium-sensing receptor (CaR) more sensitive to extracellular calcium. Because AMG-073 mimics the effects of extracellular calcium to suppress PTH secretion even in the presence of hyperphosphatemia without running the risk of causing hyperphosphatemia or hypercalcemia, it has potential benefits as a therapy for secondary hyperparathyroidism. Human embryonic kidney cells expressing the CaSR exhibit a concentration-dependent rise in cytoplasmic calcium upon exposure to AMG-073. With an IC50 of 27 nM, AMG 073 (3 nM – 1 μM) causes a concentration-dependent drop in PTH levels in bovine parathyroid cells in a buffer containing 0.5 mM of calcium.[2]

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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].

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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].

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 receiving AMG-073 orally, five out of six nephrectomized rats showed a swift, dose-dependent decrease in PTH and calcium levels, just like in normal rats. Furthermore, compared to controls, oral AMG-073 at 5 and 10 mg/kg for 4 weeks results in a significant reduction in parathyroid weight. [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.

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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 ).

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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.

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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.

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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.

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

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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]. Kidney Int Suppl . 2003 Jun:(85):S91-6.

[2]. Clin Ther . 2005 Nov;27(11):1725-51.

Cinacalcet hydrochloride is a hydrochloride derived from equimolar amounts of cinacalcet and hydrogen chloride. It has a role as a calcimimetic and a P450 inhibitor. It is functionally related to a cinacalcet.
Cinacalcet Hydrochloride is the orally bioavailable hydrochloride salt of the calcimimetic cinacalcet. Cinacalcet increases the sensitivity of calcium-sensing receptors on chief cells in the parathyroid gland to extracellular calcium, thereby reducing parathyroid hormone (PTH) secretion. A reduction in PTH levels inhibits osteoclast activity, which may result in a decrease in cortical bone turnover and bone fibrosis, and normalization of serum calcium and phosphorus levels. In addition, by reducing PTH levels, cinacalcet may reduce PSA levels; PTH appears to raise PSA levels and may increase prostate cancer cell growth.
See also: Cinacalcet (has active moiety).

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Drug Indication
Secondary hyperparathyroidism AdultsTreatment of secondary hyperparathyroidism (HPT) in adult patients with end-stage renal disease (ESRD) on maintenance dialysis therapy. Paediatric populationTreatment of secondary hyperparathyroidism (HPT) in children aged 3 years and older with end-stage renal disease (ESRD) on maintenance dialysis therapy in whom secondary HPT is not adequately controlled with standard of care therapy (see section 4. 4). Cinacalcet Accordpharma may be used as part of a therapeutic regimen including phosphate binders and/or Vitamin D sterols, as appropriate (see section 5. 1). Parathyroid carcinoma and primary hyperparathyroidism in adultsReduction of hypercalcaemia in adult patients with: parathyroid carcinoma. primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels (as defined by relevant treatment guidelines), but in whom parathyroidectomy is not clinically appropriate or is contraindicated.
Treatment of secondary hyperparathyroidism (HPT) in patients with end-stage renal disease (ESRD) on maintenance dialysis therapy. Cinacalcet Mylan may be used as part of a therapeutic regimen including phosphate binders and/or vitamin D sterols, as appropriate. Reduction of hypercalcaemia in patients with: parathyroid carcinomaprimary HPT for whom parathyroidectomywould be indicated on the basis of serum calcium levels (as defined by relevant treatment guidelines), but in whom parathyroidectomy is not clinically appropriate or is contraindicated.  
Secondary hyperparathyroidism AdultsTreatment of secondary hyperparathyroidism (HPT) in adult patients with end stage renal disease (ESRD) on maintenance dialysis therapy. Paediatric populationTreatment of secondary hyperparathyroidism (HPT) in children aged 3 years and older with end stage renal disease (ESRD) on maintenance dialysis therapy in whom secondary HPT is not adequately controlled with standard of care therapy. Mimpara may be used as part of a therapeutic regimen including phosphate binders and/or Vitamin D sterols, as appropriate. Parathyroid carcinoma and primary hyperparathyroidism in adults. Reduction of hypercalcaemia in adult patients with: parathyroid carcinoma; primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels (as defined by relevant treatment guidelines), but in whom parathyroidectomy is not clinically appropriate or is contraindicated.
Treatment of parathyroid carcinoma, Treatment of primary hyperparathyroidism , Treatment of secondary hyperparathyroidism in patients with end-stage renal disease

C22H23CLF3N

393.87

393.147

C, 67.09; H, 5.89; Cl, 9.00; F, 14.47; N, 3.56

364782-34-3

Cinacalcet; 226256-56-0; Cinacalcet-d3 hydrochloride; Cinacalcet-d3

156418

White to off-white solid powder

440.9ºCat760mmHg

175-177ºC

220.5ºC

7.334

2

4

6

27

422

1

Cl[H].FC(C1=C([H])C([H])=C([H])C(=C1[H])C([H])([H])C([H])([H])C([H])([H])N([H])[C@]([H])(C([H])([H])[H])C1=C([H])C([H])=C([H])C2=C([H])C([H])=C([H])C([H])=C12)(F)F

QANQWUQOEJZMLL-PKLMIRHRSA-N

InChI=1S/C22H22F3N.ClH/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;1H/t16-;/m1./s1

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

AMG073 HCl; Cinacalcet Hydrochloride; Sensipar; AMG-073 HCl; AMG 073 HCl; KRN1493; KRN-1493; Cinacalcet HCl; Mimpara; Regpara; cinacalcet; cinacalcet hydrochloride; Hydrochloride, Cinacalcet; KRN 1493

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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: ≥ 2.5 mg/mL (6.35 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 25.0 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.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.35 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 25.0 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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.35 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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

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