Pharmacological studies indicate that AMG 416 (etelcalcetide) is a peptide agonist of the CaR that inhibits parathyroid hormone (PTH) secretion from chief cells of the parathyroid gland. In vitro studies have shown that the CaR is the molecular target for AMG 416. [1]

When administered as an intravenous (IV) bolus in healthy rats and in rat models of renal insufficiency (e.g., 5/6 nephrectomy model), AMG 416 (etelcalcetide) effectively reduced PTH and calcium levels in normal animals, and in animals with elevated PTH due to impaired renal function. The pharmacology of AMG 416 has also been evaluated in healthy dogs after IV bolus and sustained IV infusions. AMG 416 lowered PTH levels in a dose-dependent manner in dogs. [1]

In nonclinical toxicity studies, AMG 416 (etelcalcetide) was administered to rats via daily IV bolus injection and to dogs via IV bolus every other day (based on longer plasma half-life in dogs). Chronic toxicity studies were conducted in rats for 6 months and in dogs for 9 months. A safety pharmacology study was conducted in dogs. An in vivo micronucleus study in rats used a 30-minute infusion to deliver more drug. Subcutaneous range-finding studies in rats were conducted to select doses for a carcinogenicity study. [1]
In pharmacological studies, IV bolus administration was used in rat models of renal insufficiency (e.g., 5/6 nephrectomy). [1]

Absorption, Distribution and Excretion
In patients with chronic kidney disease and secondary hyperparathyroidism requiring hemodialysis, the pharmacokinetics of eticaxicin are linear and remain unchanged over time after a single (5 to 60 mg) or multiple (2.5 to 20 mg) intravenous injection. Eticarcin exhibits a triple-exponential decay after intravenous administration. Based on population pharmacokinetic analysis, in patients with chronic kidney disease receiving eticaxicin three times a week after each 3 to 6-hour hemodialysis session, steady-state plasma concentrations are reached after 7–8 weeks, with an expected cumulative fold increase of 3 to 4 times. Eticarcin is primarily eliminated via renal excretion. 796 L/hr 7.66 L/hr Metabolisms/Metabolites Eticarcin is not metabolized by CYP450 enzymes. Eticarcinide undergoes biotransformation in the blood via reversible disulfide bond exchange with endogenous thiols, primarily forming conjugates with serum albumin. In patients with chronic kidney disease and secondary hyperparathyroidism requiring hemodialysis, the plasma exposure of the biotransformation product following a single injection of radiolabeled eticarboxyside is approximately 5 times that of eticarboxyside, and its concentration-time curve is parallel to that of eticarboxyside. The biological half-life is 3 to 4 days. The pharmacokinetics (PK) of AMG 416 (eticarboxyside) have been studied in rat models with varying degrees of renal impairment and in dogs with normal renal function. AMG 416 exhibits predictable pharmacokinetic characteristics. Studies in bilateral nephrectomy rats showed that systemic clearance decreased by approximately 3-fold after renal loss, indicating that the kidneys play a role in the clearance of AMG 416 in rats. [1]
In single-dose pharmacokinetic studies in hemodialysis patients (end-stage renal disease), AMG 416 (5-60 mg IV bolus) was eliminated from plasma in a biphasic manner. Systemic exposure (Cmax and AUC) increased in a dose-dependent manner. The estimated mean hemodialysis clearance was approximately 33 L/h at different doses. At doses of 5-40 mg, plasma AMG 416 concentrations decreased by approximately 50-78% after the first hemodialysis following dosing. At a dose of 60 mg, the decrease was 17-74%. Drug residues were observed after repeated hemodialysis, consistent with the long terminal half-life and incomplete dialysis clearance. [1]
Toxicokinetic studies in rats (up to 6 months) and dogs (9 months) showed that systemic exposure was dose-dependent. Disposal parameters (clearance, volume of distribution, half-life) appeared to be dose-independent. Mild to moderate drug accumulation was observed in rats after repeated IV injections. [1]
Tissue distribution studies in rats and dogs showed that the highest drug concentrations were recovered in the kidneys and liver. Hepatic microsomal metabolism studies indicated that AMG 416 is not metabolized by hepatic enzymes. AMG 416 does not inhibit or induce major cytochrome P450 isoenzymes. Approximately 90% of AMG 416 is bound to plasma proteins. This compound is rapidly and efficiently removed from the blood during in vitro dialysis. [1]

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation There is currently no information regarding the use of eticaxicin during lactation. Because eticaxicin is a large molecule with a molecular weight of 1047.5 Da, its concentration in breast milk may be very low. The manufacturer recommends avoiding breastfeeding during use. Especially when breastfeeding newborns or premature infants, alternative medications are recommended. ◉ Effects on Breastfed Infants As of the revision date, no relevant published information was found. ◉ Effects on Lactation and Breast Milk As of the revision date, no relevant published information was found. Protein Binding Eticarcin primarily binds to plasma albumin via reversible covalent binding. The non-covalent binding rate of eticaxicin to plasma proteins is low, with a free fraction ratio of 0.53. The concentration ratio of [14C]-eticaxicin in blood to plasma is approximately 0.6. In repeated-dose toxicity studies in rats and dogs, all adverse reactions were directly or indirectly related to the pharmacological activity of AMG 416 (eticaxitide) and were accompanied by significant dose-related hypocalcemia caused by parathyroid hormone (PTH) inhibition. No chemical toxicities unrelated to the mechanism of action of the drug were found. [1] In cardiovascular safety assessments in dogs, moderate QTc interval prolongation and other cardiovascular disturbances were observed in the high-dose group, which were caused by significant hypocalcemia. In vitro hERG assays showed that AMG 416 had no direct effect on the QT interval. [1] Effects associated with hypocalcemia/stress included clinical signs of hypocalcemia (in rats and dogs), stress-related thymic atrophy (in both animals), presumed stress-related spleen weight loss and mild gastric ulcers (in rats only), and mild erythropoiesis in dogs due to vitamin B12 malabsorption caused by hypocalcemia (which disappeared after 45 days in the chronic study). These effects were observed only at high doses, well above the expected clinical dose range. [1]
Genetic toxicity: AMG 416 was positive in 2 out of 5 tested strains in the Ames assay with/without metabolic activation. AMG 416 was negative in mammalian cell mutagenicity assays (HGPRT in CHO cells), in vitro chromosomal aberration assays in human lymphocytes, and in vivo bone marrow micronucleus assays in rats. Its overall characteristics and peptide structure are not consistent with genotoxic carcinogens. [1]
Exploratory studies of teratogenicity in rats and rabbits showed that the drug had no direct effect on embryo-fetal development at non-maternally toxic doses. The slight reduction in fetal weight gain at the highest dose was considered a secondary result of maternal toxicity. [1]
Blood compatibility studies in human blood showed that the drug did not cause hemolysis at concentrations up to 30 mg/mL. [1]
The rules for managing hepatotoxicity are as follows: If total blood volume (TBL) > 2 times the upper limit of normal (ULN) or international normalized ratio (INR) > 1.5, and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) is elevated > 3 times the upper limit of normal (ULN) (if baseline < ULN), and there is no other obvious cause, the drug must be permanently discontinued. If AST/ALT > 8 times the upper limit of normal (ULN); or > 5 times the upper limit of normal (ULN) and persists for ≥ 2 weeks; or clinical symptoms of hepatitis appear; or total blood volume (TBL) > 3 times the upper limit of normal (ULN); or alkaline phosphatase (ALP) > 8 times the upper limit of normal (ULN), the drug must be conditionally discontinued. [1]

[1]. Activation of dopamine D4 receptors by ABT-724 induces penile erection in rats. Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6758-63.

Etelcalcetide is an oligopeptide. Etelcalcetide is a calcimimetic agent used to treat secondary hyperparathyroidism (HPT) in patients undergoing hemodialysis. Etelcalcetide (trade name: Parsabiv) was approved in February 2017 for the treatment of secondary hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) undergoing hemodialysis. Etelcalcetide is a calcium-sensitive receptor agonist. Its mechanism of action is to increase the sensitivity of calcium-sensitive receptors. Etelcalcetide is a calcimimetic agent and a calcium-sensitive receptor (CaSR) agonist, composed of a synthetic peptide containing seven D-amino acids, and is used to treat secondary hyperparathyroidism (sHPT) in patients with chronic kidney disease (CKD) undergoing hemodialysis. After intravenous injection, eticascidide mimics calcium ions, allosterically binds to, and activates calcium-sensitive receptors (CaSR) expressed by the parathyroid glands. This inhibits the synthesis and secretion of parathyroid hormone (PTH), thereby lowering PTH levels and consequently reducing serum calcium and phosphorus levels. Elevated PTH levels are common in patients with chronic kidney disease (CKD), which is associated with calcium and phosphorus metabolism disorders.
See also: eticaxitinide hydrochloride (active ingredient).
Drug Indications

Eticarcinide is a calcium-sensitive receptor agonist indicated for: secondary hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) undergoing hemodialysis.
Pasapivox is indicated for the treatment of secondary hyperparathyroidism (SHPT) in adult patients with chronic kidney disease (CKD) undergoing hemodialysis.
Treatment of Hyperparathyroidism
Mechanism of Action

Eticarcinide is a calcimimetic agent that allosterically modulates the calcium-sensitive receptor (CaSR). Eticarcinide binds to CaSR, enhancing the activation of the receptor by extracellular calcium. Activation of calcium-sensitive receptors (CaSRs) on parathyroid chief cells reduces parathyroid hormone (PTH) secretion. Pharmacodynamics: Following a single intravenous bolus injection of eticaxitinide, PTH levels decreased within 30 minutes of administration. In single-dose studies, the extent and duration of PTH level reduction increased with increasing dose. In hemodialysis patients, the reduction in PTH levels was correlated with plasma eticaxitinide concentration. The decrease in PTH levels led to a decrease in calcium levels and reduced postdialysis phosphate elevation. During a 6-month dosing period, the PTH-reducing effect was maintained with three weekly intravenous bolus injections of eticaxitinide. AMG 416 (eticaxitinide), also known as KAI-4169, is a synthetic peptide composed of eight amino acids and is an agonist of the calcium-sensitive receptor (CaR), administered intravenously. Unlike the allosteric modulator cinacalcet, AMG 416 acts directly on the extracellular domain of the calcium-sensitive receptor (CaR), activating the CaR regardless of the presence of extracellular calcium ions. This drug is used to treat secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) undergoing hemodialysis. [1] Common adverse reactions to oral cinacalcet are nausea and vomiting. Intravenous administration of AMG 416 at the end of hemodialysis may help reduce nausea and vomiting. In a phase 1/2 study, the incidence was low, similar to the background incidence in this patient population. [1] One of the theoretical justifications for its development is to overcome the problem of poor adherence to oral regimens (such as cinacalcet) in hemodialysis patients due to large dosages and gastrointestinal intolerance. Intravenous administration at each dialysis session may improve patient adherence. [1]

C38H73N21O10S2

1048.26

1047.53

C, 43.54; H, 7.02; N, 28.06; O, 15.26; S, 6.12

1262780-97-1

Etelcalcetide hydrochloride; 1334237-71-6

71511839

Solid powder

1.672

18

17

36

71

1910

8

N=C(N)NCCC[C@H](C(=O)N)NC(=O)[C@@H](C)NC(=O)[C@@H](CCCNC(=N)N)NC(=O)[C@@H](CCCNC(=N)N)NC(=O)[C@@H](CCCNC(=N)N)NC(=O)[C@@H](C)NC(=O)[C@H](NC(=O)C)CSSC[C@H](N)C(O)=O

ANIAZGVDEUQPRI-ZJQCGQFWSA-N

InChI=1S/C38H73N21O10S2/c1-18(28(62)56-22(27(40)61)8-4-12-49-35(41)42)53-30(64)23(9-5-13-50-36(43)44)58-32(66)25(11-7-15-52-38(47)48)59-31(65)24(10-6-14-51-37(45)46)57-29(63)19(2)54-33(67)26(55-20(3)60)17-71-70-16-21(39)34(68)69/h18-19,21-26H,4-17,39H2,1-3H3,(H2,40,61)(H,53,64)(H,54,67)(H,55,60)(H,56,62)(H,57,63)(H,58,66)(H,59,65)(H,68,69)(H4,41,42,49)(H4,43,44,50)(H4,45,46,51)(H4,47,48,52)/t18-,19-,21+,22-,23-,24-,25-,26-/m1/s1

(2R)-3-[[(2S)-2-acetamido-3-[[(2R)-1-[[(2R)-1-[[(2R)-1-[[(2R)-1-[[(2R)-1-[[(2R)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-oxopropyl]disulfanyl]-2-aminopropanoic acid

KAI-4169; KAI4169; KAI 4169; AMG-416; AMG 416; AMG416; ONO5163; ONO 5163; ONO-5163; Etelcalcetide; Velcalcetide; Telcalcetide. Ac-D-Cys-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH2.

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)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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