Identification

Name
Etelcalcetide
Accession Number
DB12865
Type
Small Molecule
Groups
Approved, Investigational
Description

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.

Structure
Thumb
Synonyms
  • Etelcalcetida
  • Etelcalcetide
  • Velcalcetide
External IDs
AMG-416 / AMG416 / KAI-4169
Product Ingredients
IngredientUNIICASInChI Key
Etelcalcetide hydrochloride72PT5993DU1334237-71-6KHQMSZGKHGQUHG-WZDHWKSBSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ParsabivInjection, solution2.5 mg/0.5mLIntravenousAMGEN INC2017-04-03Not applicableUs
ParsabivInjection, solution10 mg/2mLIntravenousAMGEN INC2017-04-03Not applicableUs
ParsabivInjection, solution5 mg/1mLIntravenousAMGEN INC2017-04-03Not applicableUs
Categories
UNII
60ME133FJB
CAS number
1262780-97-1
Weight
Average: 1048.26
Monoisotopic: 1047.529069983
Chemical Formula
C38H73N21O10S2
InChI Key
ANIAZGVDEUQPRI-ZJQCGQFWSA-N
InChI
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
IUPAC Name
(2R)-2-amino-3-{[(2S)-2-{[(1R)-1-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-{[(1R)-1-{[(1R)-4-carbamimidamido-1-carbamoylbutyl]carbamoyl}ethyl]carbamoyl}butyl]carbamoyl}butyl]carbamoyl}butyl]carbamoyl}ethyl]carbamoyl}-2-acetamidoethyl]disulfanyl}propanoic acid
SMILES
C[C@@H](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](CSSC[C@H](N)C(O)=O)NC(C)=O)C(=O)N[C@H](CCCNC(N)=N)C(N)=O

Pharmacology

Indication

Etelcalcetide is a calcium-sensing receptor agonist indicated for: Secondary hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) on hemodialysis.

Associated Conditions
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.

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.

TargetActionsOrganism
AExtracellular calcium-sensing receptor
agonist
Human
Absorption

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

Volume of distribution

796 L

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.

Metabolism

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.

Route of elimination

Etelcalcetide is cleared by renal excretion

Half life

3 to 4 days

Clearance

7.66 L/hr

Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. FDA label [Link]
External Links
KEGG Drug
D10676
PubChem Compound
71511839
PubChem Substance
347829023
ChemSpider
32697932
ChEBI
134700
ChEMBL
CHEMBL3545184
Wikipedia
Etelcalcetide

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceSecondary Hyperparathyroidism in Patients With ESRD on Hemodialysis1
1CompletedTreatmentHyperparathyroidism, Secondary2
2CompletedTreatmentHyperparathyroidism, Secondary2
2TerminatedTreatmentHyperparathyroidism, Secondary1
3CompletedTreatmentChronic Kidney Disease (CKD) / Hyperparathyroidism, Secondary1
3CompletedTreatmentHyperparathyroidism, Secondary5
3Not Yet RecruitingTreatmentChronic Kidney Disease (CKD) / Hyperparathyroidism, Secondary1
3RecruitingTreatmentChronic Kidney Disease (CKD) / Hyperparathyroidism, Secondary1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionIntravenous10 mg/2mL
Injection, solutionIntravenous2.5 mg/0.5mL
Injection, solutionIntravenous5 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8377880No2013-02-192030-07-29Us
US9278995No2016-03-082030-07-29Us
US8999932No2015-04-072030-07-29Us
US9701712No2017-07-112030-07-29Us
US9820938No2017-11-212034-06-27Us

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.132 mg/mLALOGPS
logP-3.4ALOGPS
logP-11ChemAxon
logS-3.9ALOGPS
pKa (Strongest Acidic)-1.3ChemAxon
pKa (Strongest Basic)12.57ChemAxon
Physiological Charge4ChemAxon
Hydrogen Acceptor Count23ChemAxon
Hydrogen Donor Count22ChemAxon
Polar Surface Area557.71 Å2ChemAxon
Rotatable Bond Count36ChemAxon
Refractivity303.63 m3·mol-1ChemAxon
Polarizability107.58 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as oligopeptides. These are organic compounds containing a sequence of between three and ten alpha-amino acids joined by peptide bonds.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Oligopeptides
Alternative Parents
L-cysteine-S-conjugates / N-acyl-alpha amino acids and derivatives / Alpha amino acid amides / Alanine and derivatives / L-alpha-amino acids / N-acyl amines / Acetamides / Primary carboxylic acid amides / Guanidines / Dialkyldisulfides
show 11 more
Substituents
Alpha-oligopeptide / L-cysteine-s-conjugate / N-acyl-alpha amino acid or derivatives / Alpha-amino acid amide / Cysteine or derivatives / Alanine or derivatives / Alpha-amino acid / N-substituted-alpha-amino acid / Alpha-amino acid or derivatives / L-alpha-amino acid
show 30 more
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Phosphatidylinositol phospholipase c activity
Specific Function
Senses changes in the extracellular concentration of calcium ions. The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system.
Gene Name
CASR
Uniprot ID
P41180
Uniprot Name
Extracellular calcium-sensing receptor
Molecular Weight
120672.385 Da
References
  1. Martin KJ, Bell G, Pickthorn K, Huang S, Vick A, Hodsman P, Peacock M: Velcalcetide (AMG 416), a novel peptide agonist of the calcium-sensing receptor, reduces serum parathyroid hormone and FGF23 levels in healthy male subjects. Nephrol Dial Transplant. 2014 Feb;29(2):385-92. doi: 10.1093/ndt/gft417. Epub 2013 Nov 13. [PubMed:24235081]

Drug created on October 20, 2016 18:49 / Updated on November 05, 2018 17:50