Histrelin

Identification

Summary

Histrelin is a GnRH agonist found in subcutaneous implants used for the treatment of pediatric patients with central precocious puberty and the palliative treatment of advanced prostate cancer.

Brand Names
Supprelin, Vantas
Generic Name
Histrelin
DrugBank Accession Number
DB06788
Background

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.

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 1443.632
Monoisotopic: 1442.709519019
Chemical Formula
C70H94N18O16
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
  • Histrelin
  • 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

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.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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
Humans
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.

Adverse Effects
Medicalerrors
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AcarboseThe therapeutic efficacy of Acarbose can be decreased when used in combination with Histrelin.
AcetohexamideThe therapeutic efficacy of Acetohexamide can be decreased when used in combination with Histrelin.
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.
AjmalineThe risk or severity of QTc prolongation can be increased when Ajmaline is combined with Histrelin.
AlbiglutideThe therapeutic efficacy of Albiglutide can be decreased when used in combination with Histrelin.
AlfuzosinThe risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Histrelin.
AlimemazineThe risk or severity of QTc prolongation can be increased when Alimemazine is combined with Histrelin.
AlogliptinThe therapeutic efficacy of Alogliptin can be decreased when used in combination with Histrelin.
AmantadineThe risk or severity of QTc prolongation can be increased when Amantadine is combined with Histrelin.
Interactions
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Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Histrelin acetateNot AvailableNot AvailableNot applicable
International/Other Brands
Suprellin / Suprellin LA / Vantas
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Supprelin LAImplant50 mg/1SubcutaneousEndo Pharmaceuticals Inc.2007-05-31Not applicableUS flag
VantasImplant; Kit50 mgSubcutaneousPaladin Labs Inc2006-07-142017-04-07Canada flag
VantasImplant50 mg/1SubcutaneousValera Pharmaceuticals, Inc2007-03-092007-04-11US flag
VantasImplant50 mg/1SubcutaneousEndo Pharmaceuticals Inc.2004-11-01Not applicableUS flag

Categories

ATC Codes
L02AE05 — Histrelin
Drug Categories
Chemical TaxonomyProvided by Classyfire
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
1-hydroxy-2-unsubstituted benzenoid / 2-pyrrolidone / 3-alkylindole / Alcohol / Alpha-amino acid amide / Alpha-amino acid or derivatives / Alpha-oligopeptide / Amphetamine or derivatives / Aromatic heteropolycyclic compound / Azacycle
show 48 more
Molecular Framework
Not Available
External Descriptors
acetate salt (CHEBI:63530)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
QMG7HLD1ZE
CAS number
76712-82-8
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)-3-hydroxy-2-[(2S)-2-[(2S)-3-(1H-imidazol-4-yl)-2-{[(2S)-5-oxopyrrolidin-2-yl]formamido}propanamido]-3-(1H-indol-3-yl)propanamido]propanamido]-3-(4-hydroxyphenyl)propanamido]propanamido]-4-methylpentanamido]-5-carbamimidamidopentanoyl]-N-ethylpyrrolidine-2-carboxamide; bis(acetic acid)
SMILES
CC(O)=O.CC(O)=O.CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC1=CN(CC2=CC=CC=C2)C=N1)NC(=O)[C@H](CC1=CC=C(O)C=C1)NC(=O)[C@H](CO)NC(=O)[C@H](CC1=CNC2=C1C=CC=C2)NC(=O)[C@H](CC1=CNC=N1)NC(=O)[C@@H]1CCC(=O)N1

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. [Article]
  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. [Article]
  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. [Article]
  4. Link [Link]
KEGG Drug
D02369
PubChem Compound
56927879
PubChem Substance
347827797
ChemSpider
26606349
RxNav
50975
ChEBI
63530
ChEMBL
CHEMBL1201255
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Histrelin
FDA label
Download (1.03 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentAdenocarcinoma of the Prostate / Prostate Cancer2
3CompletedTreatmentCentral Precocious Puberty (CPP)1
3RecruitingTreatmentAdenocarcinoma, Prostate / Metastatic Malignant Neoplasm in the Bone / Stage III Prostate Cancer AJCC v8 / Stage IIIA Prostate Cancer AJCC v8 / Stage IIIB Prostate Cancer AJCC v8 / Stage IIIC Prostate Cancer AJCC v8 / Stage IVA Prostate Cancer AJCC v81
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
2Active Not RecruitingSupportive CareAdenocarcinoma of the Prostate / Prostate Cancer - Recurrent / Stage III Prostate Cancer / Stage IV Prostate Cancer1
2, 3RecruitingTreatmentMetastatic Hormone Refractory Prostate Cancer / Oligometastasis / Oligorecurrence / Prostate Cancer / Prostate Cancer - Recurrent1
Not AvailableTerminatedNot AvailableGender Dysphoria1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
ImplantSubcutaneous
ImplantSubcutaneous50 mg/1
Implant; kitSubcutaneous50 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8062652No2011-11-222026-06-16US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
logP-2.1ChemAxon
pKa (Strongest Acidic)9.49ChemAxon
pKa (Strongest Basic)11.59ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count17ChemAxon
Hydrogen Donor Count16ChemAxon
Polar Surface Area446.86 Å2ChemAxon
Rotatable Bond Count34ChemAxon
Refractivity360.07 m3·mol-1ChemAxon
Polarizability138.34 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

Targets

Drugtargets
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Kind
Protein
Organism
Humans
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 16:21 / Updated on May 07, 2021 21:36