药理学研究表明，Etelcalcetide HCl 是一种 CaR 的肽类激动剂，可抑制甲状旁腺主细胞分泌 PTH。体外研究已表明 CaR 是 Etelcalcetide HCl 的分子靶点。[1]
肝微粒体代谢研究表明，Etelcalcetide HCl 不易被肝酶代谢。评估 Etelcalcetide HCl 是否能抑制细胞色素 P450 底物代谢活性或诱导细胞色素 P450 酶的研究显示，其对任何主要的细胞色素 P450 同工酶均无影响。[1]
结合实验表明，大约 90% 的 Etelcalcetide HCl 与血浆蛋白结合。[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，Etelcalcetide HCl 能有效降低正常动物以及因肾功能受损导致 PTH 升高的动物的 PTH 和钙水平。[1]
Etelcalcetide HCl 的药理学也在健康狗身上通过静脉推注和持续静脉输注进行了评估。Etelcalcetide HCl 以剂量依赖性方式降低 PTH 水平。[1]
在涉及患有继发性甲状旁腺功能亢进 (SHPT) 的血液透析受试者的临床研究中，单次静脉注射 Etelcalcetide HCl（5-60 毫克）可产生剂量依赖性的 PTH 降低。PTH 抑制的持续时间是剂量依赖性的。单次剂量 ≥ 20 毫克可观察到血浆 PTH 在整个 3 天透析间期持续降低。PTH 的降低伴随着血清校正钙 (cCa) 的适度下降，以及透析间期血清磷升高的减弱。[1]
在一项为期 4 周的 2 期研究中，每周三次使用 Etelcalcetide HCl 5 毫克和 10 毫克治疗，治疗结束时 PTH 较基线分别降低了 36.7% 和 76.9%。[1]
在一项为期 12 周的开放标签、剂量滴定的 2 期研究中，治疗期末 PTH 的平均降幅为 53%。Etelcalcetide HCl 治疗与血清磷平均降低 10.5% 相关。[1]

进行了体外研究以确认 Etelcalcetide HCl 的分子靶点，证明其为钙敏感受体 (CaR)。[1]
专门进行了研究以评估 Etelcalcetide HCl 是否能抑制基于细胞色素 P450 的底物代谢活性或诱导细胞色素 P450 酶。这些研究表明，Etelcalcetide HCl 对所有主要的细胞色素 P450 同工酶均无影响。[1]
使用人血进行了血液相容性研究，显示 Etelcalcetide HCl 在最终浓度高达 30 毫克/毫升时没有引起溶血的可能性。[1]

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]

The pharmacokinetics (PK) of Etelcalcetide HCl has been studied in rat models with varying degrees of impaired kidney function and in dogs with normal kidney function. Etelcalcetide HCl exhibited predictable PK with good consistency among animals within each dosage group. [1]
Pharmacokinetic studies in dual-nephrectomized rats demonstrate that total body clearance decreases by approximately 3-fold in the absence of renal function, indicating that the kidney has a role in the clearance of Etelcalcetide HCl in rats. [1]
The toxicokinetics have been characterized in rats after single- and repeated IV doses for up to 6 months and in dogs for 9 months. Dose-related increases in systemic exposure were observed. Disposition parameters (e.g., clearance, volume of distribution, and half-life) appeared to be dose-independent. Slight to moderate drug accumulation was observed in rats and dogs following repeat-dose IV injections. [1]
In tissue distribution studies in rats and dogs, kidney and liver had the highest recovered drug concentrations. [1]
The compound is cleared rapidly and efficiently from blood during ex vivo dialysis. [1]
In end-stage renal disease (ESRD) subjects undergoing hemodialysis, following single IV bolus doses (5 mg to 60 mg), Etelcalcetide HCl is eliminated from plasma in a biphasic manner. Systemic exposure increased in a dose-related manner. The observed increase in total plasma exposure was proportional to dose. [1]
Etelcalcetide HCl clearance during hemodialysis generally followed a first order elimination process with estimated mean hemodialysis clearance values of approximately 33 L/h across the doses evaluated. At doses of 5 to 40 mg, there was an approximately 50-78% reduction in plasma concentrations after the first hemodialysis session. At the 60 mg dose, the apparent clearance by hemodialysis was reduced with an approximately 17-74% reduction in plasma concentration after the first session. Residual levels of drug were observed after repeat hemodialysis sessions, consistent with a long terminal half-life and incomplete drug clearance by hemodialysis. [1]

All adverse effects observed in rats and dogs were related, either directly or indirectly, to the pharmacologic activity of Etelcalcetide HCl and the expected sequelae associated with marked dose-related hypocalcemia that ensues from the nearly complete suppression of PTH secretion at high clinical-multiple doses. [1]
There were no anatomic pathology findings or other effects that suggested chemical toxicity of the Etelcalcetide HCl peptide unrelated to its mechanism of action. [1]
Cardiovascular safety evaluation in dogs revealed moderate prolongation of the QTc interval and other perturbations of cardiovascular function at high dose levels, which stemmed from pronounced hypocalcemia. An in vitro hERG assay failed to show any relationship between Etelcalcetide HCl concentration and the QT interval, confirming the absence of a direct effect. [1]
Other effects related to hypocalcemia and/or attendant stress included clinical signs characteristic of hypocalcemia (both rats and dogs), stress-related involution of the thymus (both species), presumed stress-related reduction in spleen weight and minor gastric ulceration in a few animals (rats only), and minor underproduction of red blood cells in dogs caused by apparent malabsorption of vitamin B12 resulting from hypocalcemia. These effects were seen only at the highest dose levels tested, well above the intended clinical range. [1]
Genotoxicity was evaluated. Etelcalcetide HCl was found to be positive in 2 of 5 tester strains in a bacterial reverse mutation (Ames) assay in the presence or absence of metabolic activation. However, it was negative in a mammalian cell mutagenicity assay, an in vitro chromosomal aberration assay in human peripheral blood lymphocytes, and an in vivo bone marrow micronucleus study in rats. The potential risk to humans is considered to be low. [1]
Range-finding teratogenicity studies in rats and rabbits did not reveal any direct effect on embryo-fetal development at non-maternally toxic dose levels. A minor reduction in fetal weight gain was observed at the highest dose levels in both species, considered secondary to maternal toxicity. [1]

[1]. Effect of Etelcalcetide vs Cinacalcet on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: A Randomized Clinical Trial. JAMA. 2017 Jan 10;317(2):156-164.

See also: Etelcalcetide (has active moiety).

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Drug Indication
Parsabiv is indicated for the treatment of secondary hyperparathyroidism (SHPT) in adult patients with chronic kidney disease (CKD) on haemodialysis therapy.

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Etelcalcetide HCl (AMG 416) is investigated for the treatment of secondary hyperparathyroidism (SHPT) in subjects with chronic kidney disease (CKD) on hemodialysis. [1]
It is a novel intravenous calcimimetic peptide agonist of the calcium-sensing receptor (CaR). Unlike cinacalcet (an allosteric modulator), Etelcalcetide HCl functions as a direct agonist on the CaR. [1]
The rationale for its development includes the potential to circumvent shortcomings of oral therapies (like cinacalcet), such as high pill burden and gastrointestinal intolerance (nausea/vomiting), by being administered intravenously at the end of each hemodialysis session, potentially improving adherence/compliance. [1]
In phase 2 clinical studies, the incidence of nausea and vomiting with Etelcalcetide HCl was low and generally similar to the background rate in the hemodialysis patient population. [1]
The starting dose in the phase 3 study is 5 mg IV thrice weekly at the end of hemodialysis, with dose titration up to a maximum of 15 mg based on PTH and calcium levels. [1]

C38H74CLN21O10S2

1084.72

1083.505

C, 38.22; H, 6.50; Cl, 11.88; N, 24.63; O, 13.40; S, 5.37

1334237-71-6

Etelcalcetide; 1262780-97-1

71515466

White to off-white solid powder

618

19

17

36

72

1910

8

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

KHQMSZGKHGQUHG-WZDHWKSBSA-N

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

(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

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

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮和光照。

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

配方 1 中的溶解度: 100 mg/mL (73.89 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。

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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;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。