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 delivering continuous therapeutic doses. This drug is a synthetic analog of naturally occurring GnRH with a higher potency. Histrelin implants are non-biodegradable, diffusion-controlled, hydrogel polymer reservoirs containing histrelin acetate that need to be replaced every 52 weeks.6,8

Initially, histrelin implants were developed to reduce testosterone to castration levels in patients with advanced prostate cancer.8 The Vantas product was approved by the FDA in October 2004 for the palliative treatment of this condition.8 Vantas was later discontinued by Endo Pharmaceuticals Inc. on September 21, 2021.7

GnRH agonists are the first line of treatment for children with central precocious puberty (CPP) due to their capacity to reduce LH levels and the concentration of sex steroids. As the product Supprelin LA, histrelin is indicated for the treatment of CPP in children (approved by the FDA in May 2007).6

Type
Small Molecule
Groups
Approved, Withdrawn
Structure
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).6 As the product Vantas (FDA), histrelin is indicated for the palliative treatment of advanced prostate cancer.8

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Histrelin inhibits gonadotropin secretion through the reversible down-regulation of gonadotropin-releasing hormone (GnRH) receptors in the pituitary gland and desensitization of the pituitary gonadotropes.6,8 In pediatric patients with central precocious puberty (CPP), long-term treatment with histrelin acetate suppresses the luteinizing hormone (LH) response to GnRH, causing LH levels to decrease to prepubertal levels within one month of treatment.6 This reduces ovarian and testicular steroidogenesis and slows down linear growth velocity, improving the chance of attaining predicted adult height.6 When given orally, histrelin acetate is not active.8

Both histrelin products (Vantas and Supprelin LA from Endo Pharmaceuticals) cause a transient increase in serum concentrations of estradiol in females and testosterone in both sexes during the first week of treatment.6,8 Laboratory tests are also recommended in order to monitor hormone levels. For pediatric patients with central precocious puberty (CPP) using histrelin (Supprelin LA, Endo Pharmaceuticals), LH, follicle-stimulating hormone and estradiol or testosterone should be monitored.6 In patients with advanced prostate cancer using histrelin (Vantas, Endo Pharmaceuticals), testosterone and prostate-specific antigen should be measured periodically.8 Issues such as breakage during insertion and difficulty locating and removing implants have been reported.6,8

The Supprelin LA (Endo Pharmaceuticals) product label alerts users about psychiatric events, convulsions and cases of pseudotumor cerebri (idiopathic intracranial hypertension) that have been reported in patients receiving GnRH agonists.6 The Vantas (Endo Pharmaceuticals) product label alerts users about cases of spinal cord compression and urinary tract obstruction, and an increased risk of hyperglycemia/diabetes and cardiovascular disease in men receiving GnRH agonists.8

Mechanism of action

Histrelin is a gonadotropin-releasing hormone (GnRH) agonist that acts as a potent inhibitor of gonadotropin.6,8 GnRH binds to the GnRH receptor located on the pituitary gonadotrophs, and this leads to the production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as the regulation of sexual maturation and reproductive function.4

When administered as an implant, histrelin is delivered in continuous therapeutic doses.6,8 As a GnRH agonist, this drug binds and, at first, activates the GnRH receptor. This increases the circulating levels of LH and FSH, leading to a transient increase in the concentration of gonadal steroids (testosterone and dihydrotestosterone in males and estrone and estradiol in premenopausal females).6,8 However, the continuous administration of histrelin induces the reversible down-regulation of the GnRH receptor and the desensitization of pituitary gonadotropes, which reduce LH and FSH levels.6,8

Pediatric patients with central precocious puberty (CPP) have a lower height potential. When treated with histrelin, LH levels in CPP are lowered, reducing the concentration of sex steroids.1,6 In adult males with advanced prostate cancer, histrelin reduces testosterone production to castration levels, hindering the growth of prostate cancer cells.2,3,8

TargetActionsOrganism
AGonadotropin-releasing hormone receptor
agonist
Humans
Absorption

Advanced prostate cancer patients (n = 17) that received a subcutaneous histrelin implant (Vantas, Endo Pharmaceuticals) had peak serum concentrations of 1.10 ± 0.375 ng/mL (mean ± SD) at 12 hours.8 The continuous subcutaneous release of the histrelin implant was confirmed, as serum levels were sustained throughout the 52-week dosing period. At the end of the 52-week period, the mean serum histrelin concentration was 0.13 ± 0.065 ng/mL.8 In patients that received a second implant at the end of the 52-week period, the serum histrelin concentration in the first eight weeks was similar to the one detected with the first implant. On average, the residual drug content of 41 histrelin implants (Vantas, Endo Pharmaceuticals) was 56.7 ± 7.71 mcg/day over 52 weeks.8 Compared to healthy male volunteers that received a subcutaneous bolus dose, the relative bioavailability of histrelin in patients with prostate cancer and normal renal and hepatic function was 92%.8

In children with central precocious puberty (CPP, n=47) that received a subcutaneous histrelin implant (Supprelin LA, Endo Pharmaceuticals), the median maximum serum histrelin concentration over the study period was 0.43 ng/mL, which is expected to maintain gonadotropins at prepubertal levels.6 There were no pharmacokinetic differences between patients previously treated with luteinizing hormone-releasing hormone (LHRH) agonists and those that had not.6 Food-drug interaction studies have not been performed for histrelin products.8,6 Serum histrelin concentrations are 50% higher in prostate cancer patients with mild to severe renal impairment compared to those with no renal or hepatic impairment; however, this difference is not considered clinically relevant.8

Volume of distribution

The apparent volume of distribution of histrelin following a subcutaneous bolus dose of histrelin (Vantas, Endo Pharmaceuticals, 500 mcg) in healthy volunteers was 58.4 ± 7.86 L.8

Protein binding

In an in vitro measurement, the fraction of histrelin (Vantas, Endo Pharmaceuticals) unbound in plasma was 29.5% ± 8.9% (mean ± SD).8

Metabolism

As a synthetic peptide, histrelin is expected to be metabolized by proteases throughout the body. This will likely result in several peptide fragments produced by hydrolysis.8 In an in vitro drug metabolism study using human hepatocytes, a single histrelin metabolite resulting from C-terminal dealkylation was identified.8

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Route of elimination

Drug excretion studies have not been performed for histrelin 8.

Half-life

In healthy volunteers administered a subcutaneous bolus dose of histrelin, the terminal half-life was 3.92 ± 1.01 hr (mean ± SD).8

Clearance

In prostate cancer patients (n=17) administered a histrelin implant (Vantas, Endo Pharmaceuticals) the apparent clearance was 174 ± 56.5 mL/min (mean ± SD).8

Adverse Effects
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Toxicity

There were no signs of systemic toxicity in animals injected with up to 200 mcg/kg (rats, rabbits), or 2000 mcg/kg (mice) of histrelin acetate. These concentrations represent 20 to 200 times the maximal recommended human dose of 10 mcg/kg/day.8 Patients receiving one, two or four histrelin implants (Vantas, Endo Pharmaceuticals) had similar adverse event profiles.8

No overdose cases were reported in the clinical trials of the histrelin product Supprelin LA (Vantas, Endo Pharmaceuticals). The administration of high doses of histrelin in animal studies was associated with the expected pharmacological effects.6 Since both products of histrelin are administered using implants that deliver a constant dose, accidental or intentional overdose is unlikely.

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.
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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
Supprelin / Supprelin 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.2004-11-012022-03-31US 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
H50H3S3W74
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. Ortmann O, Weiss JM, Diedrich K: Gonadotrophin-releasing hormone (GnRH) and GnRH agonists: mechanisms of action. Reprod Biomed Online. 2002;5 Suppl 1:1-7. doi: 10.1016/s1472-6483(11)60210-1. [Article]
  5. Endo Pharmaceuticals: Supprelin LA (histrelin acetate) subcutaneous implant [Link]
  6. FDA Approved Drug Products: Supprelin LA (histrelin acetate) subcutaneous implant [Link]
  7. FDA Drug Shortages: Vantas 50 mg Implantation Kit [Link]
  8. FDA Approved Drug Products: Vantas (histrelin acetate) subcutaneous implant [Link]
  9. Health Canada Approved Drug Products: Vantas (histrelin acetate) subdermal implant [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

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentAdenocarcinoma of the Prostate / Prostate Cancer2
3CompletedTreatmentCentral Precocious Puberty (CPP)1
3RecruitingTreatmentAdenocarcinoma, Prostate1
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, 3RecruitingTreatmentOligometastasis / Oligorecurrence / Prostate Cancer / Prostate Cancer - Recurrent / Refractory, metastatic hormone-refractory Prostate cancer1
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
PropertyValueSource
water solubility10 mg/mLHealth Canada Label
pKa5.3 (His-base)Health Canada Label
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

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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
References
  1. FDA Approved Drug Products: Supprelin LA (histrelin acetate) subcutaneous implant [Link]
  2. FDA Approved Drug Products: Vantas (histrelin acetate) subcutaneous implant [Link]

Drug created at September 14, 2010 16:21 / Updated at May 11, 2022 02:31