Identification

Name
Histrelin
Accession Number
DB06788
Type
Small Molecule
Groups
Approved
Description

Histrelin is a gonadotropin releasing hormone (GnRH) agonist that acts as a potent inhibitor of gonadotropin when administered as an implant that delivers continuous therapeutic doses. Following an initial stimulatory phase with increased circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to a transient increase in concentration of gonadal steroids (testosterone and dihydrotestosterone in males), continuous administration of histrelin acetate results in decreased levels of LH and FSH due to a reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropes.

As the product Supprelin LA (FDA), histrelin is indicated for the treatment of children with central precocious puberty (CPP). As the product Vantas (FDA), histrelin is indicated for the palliative treatment of advanced prostate cancer.

Structure
Thumb
Synonyms
  • [(im-Bzl)-D-His6,Pro9-NEt]-gonadotropin releasing hormone
  • 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-1-benzyl-D-histidyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide
  • 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-Nτ-benzyl-D-histidyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide
  • histrelina
  • histreline
  • histrelinum
  • L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-Nim-benzyl-histidyl-L-leucyl-L-arginyl-L-proline ethylamide
External IDs
ORF 17070 / ORF-17070 / ORF17070 / RWJ 17070 / RWJ-17070 / RWJ17070
Product Ingredients
IngredientUNIICASInChI Key
Histrelin acetateNot AvailableNot AvailableNot applicable
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Supprelin LAImplant50 mg/1SubcutaneousEndo Pharmaceuticals Solutions Inc.2007-05-31Not applicableUs
VantasImplant; Kit50 mgSubcutaneousPaladin Labs Inc2006-07-142017-04-07Canada
VantasImplant50 mg/1SubcutaneousEndo Pharmaceuticals Solutions Inc.2004-11-01Not applicableUs
VantasImplant50 mg/1SubcutaneousValera Pharmaceuticals, Inc2007-03-092007-04-11Us
Categories
UNII
QMG7HLD1ZE
CAS number
76712-82-8
Weight
Average: 1443.632
Monoisotopic: 1442.709519019
Chemical Formula
C70H94N18O16
InChI Key
BKEMVGVBBDMHKL-VYFXDUNUSA-N
InChI
InChI=1S/C66H86N18O12.2C2H4O2/c1-4-70-64(95)55-17-11-25-84(55)65(96)48(16-10-24-71-66(67)68)76-58(89)49(26-38(2)3)77-62(93)53(30-43-34-83(37-74-43)33-40-12-6-5-7-13-40)81-59(90)50(27-39-18-20-44(86)21-19-39)78-63(94)54(35-85)82-60(91)51(28-41-31-72-46-15-9-8-14-45(41)46)79-61(92)52(29-42-32-69-36-73-42)80-57(88)47-22-23-56(87)75-47;2*1-2(3)4/h5-9,12-15,18-21,31-32,34,36-38,47-55,72,85-86H,4,10-11,16-17,22-30,33,35H2,1-3H3,(H,69,73)(H,70,95)(H,75,87)(H,76,89)(H,77,93)(H,78,94)(H,79,92)(H,80,88)(H,81,90)(H,82,91)(H4,67,68,71);2*1H3,(H,3,4)/t47-,48-,49-,50-,51-,52-,53+,54-,55-;;/m0../s1
IUPAC Name
(2S)-1-[(2S)-2-{[(2S)-2-{[(2R)-3-(1-benzyl-1H-imidazol-4-yl)-2-{[(2S)-2-{[(2S)-1,3-dihydroxy-2-{[(2S)-1-hydroxy-2-{[(2S)-1-hydroxy-2-({hydroxy[(2S)-5-hydroxy-3,4-dihydro-2H-pyrrol-2-yl]methylidene}amino)-3-(1H-imidazol-5-yl)propylidene]amino}-3-(1H-indol-3-yl)propylidene]amino}propylidene]amino}-1-hydroxy-3-(4-hydroxyphenyl)propylidene]amino}-1-hydroxypropylidene]amino}-1-hydroxy-4-methylpentylidene]amino}-5-carbamimidamidopentanoyl]-N-ethylpyrrolidine-2-carboximidic acid; bis(acetic acid)
SMILES
CC(O)=O.CC(O)=O.[H][C@@](CO)(N=C(O)[C@]([H])(CC1=CNC2=CC=CC=C12)N=C(O)[C@]([H])(CC1=CN=CN1)N=C(O)[C@]1([H])CCC(O)=N1)C(O)=N[C@@]([H])(CC1=CC=C(O)C=C1)C(O)=N[C@]([H])(CC1=CN(CC2=CC=CC=C2)C=N1)C(O)=N[C@@]([H])(CC(C)C)C(O)=N[C@@]([H])(CCCNC(N)=N)C(=O)N1CCC[C@@]1([H])C(O)=NCC

Pharmacology

Indication

As the product Supprelin LA (FDA), histrelin is indicated for the treatment of children with central precocious puberty (CPP). As the product Vantas (FDA), histrelin is indicated for the palliative treatment of advanced prostate cancer.

Associated Conditions
Pharmacodynamics

Long-term treatment with histrelin acetate suppresses the LH response to GnRH causing LH levels to decrease to prepubertal levels within 1 month of treatment. As a result, serum concentrations of sex steroids (estrogen or testosterone) also decrease. In the treatment of Central Precocious Puberty, this is relevant as secondary sexual development ceases to progress in most patients. Additionally, linear growth velocity is slowed which improves the chance of attaining predicted adult height.

Mechanism of action

Histrelin is a gonadotropin releasing hormone (GnRH) agonist that acts as a potent inhibitor of gonadotropin when administered as an implant that delivers continuous therapeutic doses. Following an initial stimulatory phase with increased circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to a transient increase in concentration of gonadal steroids (testosterone and dihydrotestosterone in males), continuous administration of histrelin acetate results in decreased levels of LH and FSH due to a reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropes.

TargetActionsOrganism
AGonadotropin-releasing hormone receptor
agonist
Human
Absorption

Following subcutaneous insertion of one histrelin implant as the product Vantas in advanced prostate cancer patients (n = 17), peak serum concentrations of 1.10 ± 0.375 ng/mL (mean ± SD) occurred at a median of 12 hours. Continuous subcutaneous release was evident, as serum levels were sustained throughout the 52 week dosing period (see Figure 1). The mean serum histrelin concentration at the end of the 52 week treatment duration was 0.13 ± 0.065 ng/mL.

Volume of distribution

The apparent volume of distribution of histrelin following a subcutaneous bolus dose of histrelin as the product Vantas (500 mcg) in healthy volunteers was 58.4 ± 7.86 L

Protein binding

For the product Vantas, the fraction of drug unbound in plasma measured in vitro was 29.5% ± 8.9% (mean ± SD).

Metabolism

An in vitro drug metabolism study using human hepatocytes identified a single histrelin metabolite resulting from C-terminal dealkylation. Peptide fragments resulting from hydrolysis are also likely metabolites.

Route of elimination
Not Available
Half life
Not Available
Clearance

The apparent clearance following a 50 mg (as histrelin acetate) Vantas implant in 17 prostate cancer patients was 174 mL/min.

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

Interactions

Drug Interactions
DrugInteraction
2,4-thiazolidinedioneThe therapeutic efficacy of 2,4-thiazolidinedione can be decreased when used in combination with Histrelin.
AbexinostatThe risk or severity of QTc prolongation can be increased when Histrelin is combined with Abexinostat.
AcarboseThe therapeutic efficacy of Acarbose can be decreased when used in combination with Histrelin.
AcebutololThe risk or severity of QTc prolongation can be increased when Histrelin is combined with Acebutolol.
AceprometazineThe risk or severity of QTc prolongation can be increased when Histrelin is combined with Aceprometazine.
AcetohexamideThe therapeutic efficacy of Acetohexamide can be decreased when used in combination with Histrelin.
AcetyldigoxinThe risk or severity of QTc prolongation can be increased when Histrelin is combined with Acetyldigoxin.
AcrivastineThe risk or severity of QTc prolongation can be increased when Histrelin is combined with Acrivastine.
AdenosineThe risk or severity of QTc prolongation can be increased when Histrelin is combined with Adenosine.
AICA ribonucleotideThe therapeutic efficacy of AICA ribonucleotide can be decreased when used in combination with Histrelin.
Food Interactions
Not Available

References

General References
  1. Lewis KA, Eugster EA: Experience with the once-yearly histrelin (GnRHa) subcutaneous implant in the treatment of central precocious puberty. Drug Des Devel Ther. 2009 Sep 21;3:1-5. [PubMed:19920916]
  2. Shore N, Cookson MS, Gittelman MC: Long-term efficacy and tolerability of once-yearly histrelin acetate subcutaneous implant in patients with advanced prostate cancer. BJU Int. 2012 Jan;109(2):226-32. doi: 10.1111/j.1464-410X.2011.10370.x. Epub 2011 Aug 18. [PubMed:21851539]
  3. Djavan B, Schlegel P, Salomon G, Eckersberger E, Sadri H, Graefen M: Analysis of testosterone suppression in men receiving histrelin, a novel GnRH agonist for the treatment of prostate cancer. Can J Urol. 2010 Aug;17(4):5265-71. [PubMed:20735905]
  4. Link [Link]
External Links
KEGG Drug
D02369
PubChem Compound
56927879
PubChem Substance
347827797
ChEBI
63530
ChEMBL
CHEMBL1201255
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Histrelin
ATC Codes
L02AE05 — Histrelin
FDA label
Download (1.03 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2RecruitingSupportive CareAdenocarcinoma of the Prostate / Recurrent Prostate Cancer / Stage III Prostate Cancer / Stage IV Prostate Cancer1
3CompletedTreatmentAdenocarcinoma of the Prostate / Prostate Cancer2
3CompletedTreatmentCentral Precocious Puberty (CPP)1
3RecruitingTreatmentCastration Levels of Testosterone / Metastatic Prostatic Adenocarcinoma / Stage IV Prostate Cancer AJCC v8 / Stage IVA Prostate Cancer AJCC v8 / Stage IVB Prostate Cancer AJCC v81
Not AvailableRecruitingNot AvailableGender Dysphoria1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
ImplantSubcutaneous50 mg/1
Implant; kitSubcutaneous50 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8062652No2011-11-222026-06-16Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.162 mg/mLALOGPS
logP2.21ALOGPS
logP3.39ChemAxon
logS-3.9ALOGPS
pKa (Strongest Acidic)2.71ChemAxon
pKa (Strongest Basic)11.9ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count26ChemAxon
Hydrogen Donor Count16ChemAxon
Polar Surface Area478.27 Å2ChemAxon
Rotatable Bond Count34ChemAxon
Refractivity365.33 m3·mol-1ChemAxon
Polarizability139.23 Å3ChemAxon
Number of Rings8ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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
Tyrosine and derivatives / Phenylalanine and derivatives / Histidine and derivatives / Leucine and derivatives / N-acyl-alpha amino acids and derivatives / Proline and derivatives / Tryptamines and derivatives / Serine and derivatives / Alpha amino acid amides / Amphetamines and derivatives
show 23 more
Substituents
Alpha-oligopeptide / Tyrosine or derivatives / Phenylalanine or derivatives / Histidine or derivatives / Leucine or derivatives / N-acyl-alpha amino acid or derivatives / Proline or derivatives / Triptan / Alpha-amino acid amide / Serine or derivatives
show 48 more
Molecular Framework
Not Available
External Descriptors
acetate salt (CHEBI:63530)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Peptide binding
Specific Function
Receptor for gonadotropin releasing hormone (GnRH) that mediates the action of GnRH to stimulate the secretion of the gonadotropic hormones luteinizing hormone (LH) and follicle-stimulating hormone...
Gene Name
GNRHR
Uniprot ID
P30968
Uniprot Name
Gonadotropin-releasing hormone receptor
Molecular Weight
37730.355 Da

Drug created on September 14, 2010 10:21 / Updated on November 02, 2018 08:47