药理学研究表明，AMG 416（依特卡肽）是一种钙敏感受体的肽类激动剂，可抑制甲状旁腺主细胞的甲状旁腺激素分泌。体外研究表明钙敏感受体是AMG 416的分子靶点。[1]

在健康大鼠和肾功能不全大鼠模型（例如，5/6肾切除模型）中静脉推注给药时，AMG 416（依特卡肽）能有效降低正常动物以及因肾功能受损而PTH升高的动物的PTH和钙水平。该药在健康犬中的药理作用也通过静脉推注和持续静脉输注进行了评估。AMG 416能以剂量依赖的方式降低犬的PTH水平。[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
The pharmacokinetics of etelcalcetide is linear and does not change over time following single (5 to 60 mg) and multiple intravenous doses (2.5 to 20 mg) in chronic kidney disease patients with secondary hyperparathyroidism requiring hemodialysis. Etelcalcetide exhibited tri-exponential decay following intravenous administration. Based on population pharmacokinetic analysis, following three times a week intravenous dosing at the end of each 3- to 6-hour hemodialysis session in chronic kidney disease patients, etelcalcetide plasma levels reached steady state in 7-8 weeks after dosing with a predicted accumulation ratio of 3- to 4-fold
Etelcalcetide is cleared by renal excretion
796 L
7.66 L/hr

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Metabolism / Metabolites
Etelcalcetide is not metabolized by CYP450 enzymes. Etelcalcetide is biotransformed in blood by reversible disulfide exchange with endogenous thiols to predominantly form conjugates with serum albumin. Following a single radiolabeled dose of etelcalcetide in chronic kidney disease patients with secondary hyperparathyroidism requiring hemodialysis, the plasma exposure of biotransformation products is approximately 5-fold higher than that of etelcalcetide and their concentration-time course parallels that of etelcalcetide.

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Biological Half-Life
3 to 4 days

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The pharmacokinetics (PK) of AMG 416 (etelcalcetide) has been studied in rat models with varying degrees of impaired kidney function and in dogs with normal kidney function. AMG 416 exhibited predictable PK. Studies in dual-nephrectomized rats showed total body clearance decreased approximately 3-fold in the absence of renal function, indicating the kidney has a role in AMG 416 clearance in rats. [1]
In single-dose PK studies in hemodialysis subjects (ESRD), AMG 416 (5-60 mg IV bolus) was eliminated from plasma in a biphasic manner. Systemic exposure (Cmax and AUC) increased dose-proportionally. The estimated mean hemodialysis clearance was approximately 33 L/h across doses. At doses of 5-40 mg, plasma AMG 416 concentrations were reduced by approximately 50-78% after the first hemodialysis session post-dose. At 60 mg, the reduction was 17-74%. Residual drug levels were observed after repeat hemodialysis sessions, consistent with a long terminal half-life and incomplete clearance by dialysis. [1]
Toxicokinetics in rats (up to 6 months) and dogs (9 months) showed dose-related increases in systemic exposure. Disposition parameters (clearance, volume of distribution, half-life) appeared dose-independent. Slight to moderate drug accumulation was observed following repeat-dose IV injections in rats. [1]
Tissue distribution studies in rats and dogs showed the highest recovered drug concentrations in kidney and liver. Hepatic microsomal metabolism studies suggest AMG 416 is not metabolized by hepatic enzymes. AMG 416 did not inhibit or induce major cytochrome P450 isoforms. Approximately 90% of AMG 416 is bound to plasma proteins. The compound is cleared rapidly and efficiently from blood during ex vivo dialysis. [1]

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on etelcalcetide during breastfeeding. Because etelcalcetide is a large molecule with a molecular weight of 1047.5 Da, the amount in milk is likely to be low. The manufacturer recommends that breastfeeding be avoided during use. An alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ 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
Etelcalcetide is predominately bound to plasma albumin by reversible covalent binding. Non-covalent binding of etelcalcetide to plasma proteins is low with a fraction unbound ratio of 0.53. The ratio of blood-to-plasma [14C]-etelcalcetide concentrations is approximately 0.6.

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In repeat-dose toxicity studies in rats and dogs, all adverse effects were related directly or indirectly to the pharmacologic activity of AMG 416 (etelcalcetide) and marked dose-related hypocalcemia from PTH suppression. No anatomic pathology findings suggested chemical toxicity unrelated to its mechanism. [1]
Cardiovascular safety evaluation in dogs revealed moderate QTc prolongation and other cardiovascular perturbations at high dose levels, stemming from pronounced hypocalcemia. An in vitro hERG assay showed no direct effect of AMG 416 on the QT interval. [1]
Effects related to hypocalcemia/stress included clinical signs of hypocalcemia (rats and dogs), stress-related thymic involution (both species), presumed stress-related spleen weight reduction and minor gastric ulceration (rats only), and minor underproduction of red blood cells in dogs due to apparent vitamin B12 malabsorption from hypocalcemia (not persistent beyond Day 45 in chronic study). These were seen only at high doses well above the intended clinical range. [1]
Genotoxicity: AMG 416 was positive in 2 of 5 tester strains in a bacterial reverse mutation (Ames) assay with/without metabolic activation. It was negative in a mammalian cell mutagenicity assay (HGPRT in CHO cells), an in vitro chromosomal aberration assay in human lymphocytes, and an in vivo bone marrow micronucleus study in rats. The overall profile and peptide structure are not consistent with a genotoxic carcinogen. [1]
Range-finding teratogenicity studies in rats and rabbits showed no direct effect on embryo-fetal development at non-maternally toxic doses. A minor reduction in fetal weight gain at the highest doses was considered secondary to maternal toxicity. [1]
A blood compatibility study with human blood showed no potential to cause hemolysis at concentrations up to 30 mg/mL. [1]
Hepatotoxicity management rules are defined: Permanent discontinuation is required if TBL > 2x ULN or INR >1.5, AND increased AST/ALT >3x ULN (if baseline 8x ULN; or >5x ULN for ≥2 weeks; or clinical signs of hepatitis; or TBL >3x ULN; or ALP >8x ULN. [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 drug for the treatment of secondary hyperparathyroidism in patients undergoing hemodialysis. Etelcalcetide was approved (trade name Parsabiv) for the treatment of secondary hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) on hemodialysis in February, 2017.
Etelcalcetide is a Calcium-sensing Receptor Agonist. The mechanism of action of etelcalcetide is as an Increased Calcium-sensing Receptor Sensitivity.
Etelcalcetide is a calcimimetic and calcium-sensing receptor (CaSR) agonist composed of a synthetic peptide comprised of seven D-amino acids that can be used to treat secondary hyperparathyroidism (sHPT) in hemodialysis patients with chronic kidney disease (CKD). Upon intravenous administration, etelcalcetide mimics calcium and allosterically binds to and activates the CaSR expressed by the parathyroid gland. This suppresses the synthesis and secretion of parathyroid hormone (PTH), thereby reducing PTH levels and lowering serum calcium and phosphorus levels. Elevated PTH is often observed in patients with CKD and is associated with dysregulated calcium-phosphate homeostasis.
See also: Etelcalcetide Hydrochloride (active moiety of).

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Drug Indication
Etelcalcetide is a calcium-sensing receptor agonist indicated for: Secondary hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) on hemodialysis.
Parsabiv is indicated for the treatment of secondary hyperparathyroidism (SHPT) in adult patients with chronic kidney disease (CKD) on haemodialysis therapy.
Treatment of hyperparathyroidism

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Mechanism of Action
Etelcalcetide is a calcimimetic agent that allosterically modulates the calcium-sensing receptor (CaSR). Etelcalcetide binds to the CaSR and enhances activation of the receptor by extracellular calcium. Activation of the CaSR on parathyroid chief cells decreases PTH secretion.

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Pharmacodynamics
Following a single intravenous bolus administration of etelcalcetide, PTH levels decreased within 30 minutes post dose. In the single-dose study, the extent and duration of the reduction in PTH increased with increasing dose. Reduction in PTH levels correlated with plasma etelcalcetide concentrations in hemodialysis patients. The reduction in PTH resulted in reductions in calcium and attenuation of post-dialytic phosphate elevation. The effect of reducing PTH levels was maintained throughout the 6-month dosing period when etelcalcetide was administered by intravenous bolus three times a week.

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AMG 416 (etelcalcetide), also known as KAI-4169, is an eight-amino acid synthetic peptide agonist of the calcium-sensing receptor (CaR) administered intravenously. Unlike the allosteric modulator cinacalcet, it functions as a direct agonist on the extracellular domain of the CaR, activating it both in the presence and absence of extracellular calcium ions. It is developed for the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) on hemodialysis. [1]
Nausea and vomiting are common adverse reactions with oral cinacalcet. AMG 416, given IV at the end of hemodialysis, may be associated with reduced nausea and vomiting. Rates in phase 1/2 studies were low and similar to background rates in this patient population. [1]
The rationale for its development includes circumventing sub-optimal adherence to oral regimens (like cinacalcet) in hemodialysis patients, due to high pill burden and GI intolerance. IV administration with each dialysis session may improve adherence/compliance. [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

608.31

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)

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
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