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Purity: ≥98%
Etelcalcetide HCl (formerly known as ONO-5163; AMG-416, KAI-4169 and velcalcetide, Parsabiv), the hydrochloride salt of Etelcalcetide, is an agonist of calcium-sensing receptor that has been approved by FDA in 2017 as a calcimimetic drug for the treatment of secondary hyperparathyroidism in CKD (chronic kidney disease) patients undergoing hemodialysis.
| ln Vitro |
Pharmacological studies indicate that Etelcalcetide HCl is a peptide agonist of the CaR that inhibits PTH secretion from chief cells of the parathyroid gland. In vitro studies have shown that the CaR is the molecular target for Etelcalcetide HCl. [1]
Hepatic microsomal metabolism studies suggest that Etelcalcetide HCl is not subject to metabolism by hepatic enzymes. Studies to assess whether Etelcalcetide HCl could inhibit cytochrome P450-based substrate metabolizing activities or induce cytochrome P450 enzymes showed no effect on any of the major cytochrome P450 isoforms. [1] Binding experiments indicate that approximately 90% of Etelcalcetide HCl is bound to plasma proteins. [1] |
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| ln Vivo |
When administered as an intravenous (IV) bolus in healthy rats and in rat models of renal insufficiency (e.g., 5/6 nephrectomy model), Etelcalcetide HCl effectively reduced PTH and calcium levels in normal animals, and in animals with elevated PTH due to impaired renal function. [1]
The pharmacology of Etelcalcetide HCl has also been evaluated in healthy dogs after IV bolus and sustained IV infusions. Etelcalcetide HCl lowered PTH levels in a dose-dependent manner. [1] In clinical studies involving hemodialysis subjects with secondary hyperparathyroidism (SHPT), single IV doses of Etelcalcetide HCl (5-60 mg) produced dose-dependent reductions in PTH. The duration of PTH suppression was dose-dependent. Sustained reductions in plasma PTH through the 3-day interdialytic period were observed with single doses ≥ 20 mg. The reduction in PTH was associated with modest decreases in serum corrected calcium (cCa) and with an attenuation of the rise in serum phosphorus during the interdialytic period. [1] In a 4-week, phase 2 study, treatment with Etelcalcetide HCl 5 mg and 10 mg thrice weekly resulted in 36.7% and 76.9% reductions from baseline in PTH, respectively, at the end of treatment. [1] In a 12-week, open-label, dose titration phase 2 study, the mean reduction in PTH at the end of the treatment period was 53%. Etelcalcetide HCl treatment was associated with a 10.5% mean reduction in serum phosphorus. [1] |
| Enzyme Assay |
In vitro studies were conducted to confirm the molecular target of Etelcalcetide HCl, demonstrating it to be the calcium-sensing receptor (CaR). [1]
Studies were conducted specifically to assess whether Etelcalcetide HCl could inhibit cytochrome P450-based substrate metabolizing activities or induce cytochrome P450 enzymes. These studies showed no effect of Etelcalcetide HCl on any of the major cytochrome P450 isoforms. [1] A blood compatibility study was performed with human blood, showing no potential to cause hemolysis at final concentrations of Etelcalcetide HCl up to 30 mg/mL. [1] |
| Animal Protocol |
Nonclinical toxicity studies were performed with IV bolus injection in rats and dogs. The IV doses were administered daily to rats or every other day to dogs (based on the longer plasma half-life and pharmacodynamic duration of action in dogs). These included dose range-finding investigations, definitive repeat-dose 4-week toxicity studies, and chronic toxicity studies in rats and dogs of 6 and 9 months duration, respectively. [1]
A comprehensive safety pharmacology study was conducted in dogs. [1] An in vivo micronucleus study in rats was performed with a 30-minute infusion. [1] Range-finding embryo-fetal toxicity (teratogenicity; Segment II) studies were conducted in rats and rabbits. [1] Subcutaneous range-finding studies in rats were performed to select dose levels for a 2-year carcinogenicity study in rats. [1] |
| ADME/Pharmacokinetics |
The pharmacokinetics (PK) of Etelcalcetide HCl have been studied in rat models with varying degrees of renal impairment and in dogs with normal renal function. Etelcalcetide HCl exhibits predictable pharmacokinetic characteristics with good consistency among animals across dose groups. [1]
Pharmacokinetic studies in nephrectomy rats showed that total clearance decreased by approximately 3-fold with renal impairment, indicating that the kidneys play a role in the clearance of Etelcalcetide HCl in rats. [1] Toxicokinetic characteristics have been characterized in rats for up to 6 months after single and repeated intravenous administration, and in dogs for up to 9 months. Systemic exposure was observed to increase with increasing dose. In vivo distribution parameters (e.g., clearance, volume of distribution, and half-life) appeared to be dose-independent. Mild to moderate drug accumulation was observed in rats and dogs after repeated intravenous administration. [1] In tissue distribution studies in rats and dogs, the highest drug recovery concentrations were observed in the kidneys and liver. [1] This compound is rapidly and effectively cleared from the blood during extracorporeal dialysis. [1] In patients with end-stage renal disease (ESRD) undergoing hemodialysis, eticascutide hydrochloride is eliminated from plasma in a biphasic manner following a single intravenous bolus (5 mg to 60 mg). Systemic exposure increases in a dose-dependent manner. The observed increase in total plasma exposure is dose-dependent. [1] Eticarcinoidide hydrochloride is typically cleared during hemodialysis following a first-order elimination process, with an estimated mean hemodialysis clearance of approximately 33 L/h over the evaluated dose range. At doses of 5 to 40 mg, plasma concentrations decrease by approximately 50% to 78% after the first hemodialysis. At a dose of 60 mg, apparent clearance from hemodialysis decreases, with plasma concentrations decreasing by approximately 17% to 74% after the first dialysis. Drug residues were observed after repeated hemodialysis, which is consistent with the long terminal half-life and incomplete clearance by hemodialysis. [1] |
| Toxicity/Toxicokinetics |
All adverse reactions observed in rats and dogs were directly or indirectly related to the pharmacological activity of Etelcalcetide HCl and were associated with the expected sequelae of significant dose-related hypocalcemia, which was caused by near-complete inhibition of PTH secretion at high clinical doses. [1] No anatomical pathological results or other effects were found that suggest that the peptide Etelcalcetide HCl has chemical toxicity unrelated to its mechanism of action. [1] Cardiovascular safety assessments in dogs showed moderate QTc interval prolongation at high dose levels, accompanied by other cardiovascular dysfunctions, all of which were due to significant hypocalcemia. In vitro hERG assays failed to show any association between Etelcalcetide HCl concentration and QT interval, confirming that it had no direct effect. [1] Other effects associated with hypocalcemia and/or stress include characteristic clinical signs of hypocalcemia (in both rats and dogs), stress-related thymic atrophy (in both animals), presumed stress-related spleen weight loss, and mild gastric ulceration in a few animals (rat only), as well as mild erythropoiesis in dogs due to vitamin B12 malabsorption caused by hypocalcemia. These effects were observed only at the highest dose level tested, well above the expected clinical dose range. [1] Genotoxicity was assessed. With or without metabolic activation, Etelcalcetide HCl was positive in the bacterial reversion mutation (Ames) test in 2 of the 5 tested strains. However, results were negative in mammalian cell mutagenicity assays, in vitro chromosomal aberration assays in human peripheral blood lymphocytes, and in vivo bone marrow micronucleus assays in rats. The potential risk to humans is considered low. [1]
Exploratory studies of teratogenicity in rats and rabbits showed no direct effects on embryo-fetal development at non-maternally toxic dose levels. Slightly reduced fetal weight gain was observed at the highest dose levels in both animals, which was considered a secondary consequence of maternal toxicity. [1] |
| References | |
| Additional Infomation |
See also: eticaxidide (with active moiety).
Drug indications Pasabivif is indicated for the treatment of secondary hyperparathyroidism (SHPT) in adult patients with chronic kidney disease (CKD) undergoing hemodialysis. Eticarcinide hydrochloride (AMG 416) is being investigated for the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) undergoing hemodialysis. [1] It is a novel intravenously administered calcium-sensitive receptor (CaR) agonist with calcimimetic activity. Unlike cinacalcet (an allosteric modulator), eticaxidide hydrochloride directly agonizes CaR. [1] The idea behind this drug is that by administering it intravenously after each hemodialysis session, it can overcome the disadvantages of oral medications (such as cinacalcet), such as the burden of medication and gastrointestinal intolerance (nausea/vomiting), thereby potentially improving patient compliance. [1] In the Phase II clinical trial, the incidence of nausea and vomiting caused by eticaxitinide hydrochloride was low and similar to the background incidence in the hemodialysis patient population. [1] In the Phase III trial, the starting dose was 5 mg intravenously three times a week after each hemodialysis session, with the dose adjusted according to parathyroid hormone (PTH) and calcium levels, up to a maximum of 15 mg. [1] |
| Molecular Formula |
C38H74CLN21O10S2
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|---|---|
| Molecular Weight |
1084.72
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| Exact Mass |
1083.505
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| Elemental Analysis |
C, 38.22; H, 6.50; Cl, 11.88; N, 24.63; O, 13.40; S, 5.37
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| CAS # |
1334237-71-6
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| Related CAS # |
Etelcalcetide; 1262780-97-1
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| PubChem CID |
71515466
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
19
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| Hydrogen Bond Acceptor Count |
17
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| Rotatable Bond Count |
36
|
| Heavy Atom Count |
72
|
| Complexity |
1910
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| Defined Atom Stereocenter Count |
8
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| SMILES |
Cl.S(C[C@H](C(N[C@H](C)C(N[C@@H](C(N[C@@H](C(N[C@@H](C(N[C@H](C)C(N[C@@H](C(N)=O)CCC/N=C(\N)/N)=O)=O)CCC/N=C(\N)/N)=O)CCC/N=C(\N)/N)=O)CCC/N=C(\N)/N)=O)=O)NC(C)=O)SC[C@@H](C(=O)O)N
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| InChi Key |
KHQMSZGKHGQUHG-WZDHWKSBSA-N
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| InChi Code |
InChI=1S/C38H73N21O10S2.ClH/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);1H/t18-,19-,21+,22-,23-,24-,25-,26-;/m1./s1
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| Chemical Name |
(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;hydrochloride
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| Synonyms |
Velcalcetide HCl; AMG-416 HCl; ONO5163; ONO-5163 HCl; AMG416; KAI 4169; KAI4169; AMG 416; KAI-4169; ONO 5163; Etelcalcetide; Velcalcetide; trade name Parsabiv; Telcalcetide; Ac-D-Cys-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH2 HCl
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| HS Tariff Code |
2934.99.9001
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| Storage |
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 (e.g. under nitrogen), avoid exposure to moisture and light. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 100 mg/mL (73.89 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
(Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.9219 mL | 4.6095 mL | 9.2190 mL | |
| 5 mM | 0.1844 mL | 0.9219 mL | 1.8438 mL | |
| 10 mM | 0.0922 mL | 0.4609 mL | 0.9219 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03969329 | Recruiting | Drug: Etelcalcetide | Secondary Hyperparathyroidism | Amgen | December 20, 2019 | Phase 3 |
| NCT03633708 | Recruiting | Drug: Etelcalcetide | Secondary Hyperparathyroidism Chronic Kidney Disease |
Amgen | April 29, 2019 | Phase 3 |
| NCT03960437 | Completed | Drug: Etelcalcetide | Renal Osteodystrophy Vascular Calcification |
Thomas Nickolas, MD MS | September 6, 2018 | Phase 2 |
| NCT03795558 | Completed | Drug: Etelcalcetide | End Stage Renal Disease | Prim. Priv. Doz. Dr. Daniel Cejka | May 1, 2019 | Phase 2 |
| NCT01254565 | Completed | Drug: Etelcalcetide Drug: Placebo |
Secondary Hyperparathyroidism | KAI Pharmaceuticals | February 20, 2011 | Phase 2 |
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