Pasireotide

Identification

Name
Pasireotide
Accession Number
DB06663
Type
Small Molecule
Groups
Approved
Description

Pasireotide is a synthetic long-acting cyclic hexapeptide with somatostatin-like activity. It is marketed as a diaspartate salt called Signifor, which is used in the treatment of Cushing's disease.

Structure
Thumb
Synonyms
  • cyclo((4R)-4-(2-aminoethylcarbamoyloxy)-L-prolyl-L-phenylglycyl-D-tryptophyl-L-lysyl-4-O-benzyl-L-tyrosyl-L- phenylalanyl-)
  • Pasireotida
  • Pasiréotide
  • Pasireotidum
External IDs
SOM 230 / SOM-230 / SOM230
Product Ingredients
IngredientUNIICASInChI Key
Pasireotide diaspartateI4P76SY3N4820232-50-6NEEFMPSSNFRRNC-HQUONIRXSA-N
Pasireotide pamoate04F55A7UZ3396091-79-5HSXBEUMRBMAVDP-QKXVGOHISA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
SigniforSolution0.3 mgSubcutaneousNovartis2013-11-26Not applicableCanada
SigniforInjection, solution0.6 mgSubcutaneousNovartis Europharm Limited2012-04-24Not applicableEu
SigniforInjection, solution0.3 mgSubcutaneousNovartis Europharm Limited2012-04-24Not applicableEu
SigniforInjection, powder, for suspension60 mgIntramuscularNovartis Europharm Limited2012-04-24Not applicableEu
SigniforInjection, powder, for suspension20 mgIntramuscularNovartis Europharm Limited2012-04-24Not applicableEu
SigniforInjection, solution0.9 mgSubcutaneousNovartis Europharm Limited2012-04-24Not applicableEu
SigniforInjection, solution0.6 mgSubcutaneousNovartis Europharm Limited2012-04-24Not applicableEu
SigniforInjection.3 mg/mLSubcutaneousNovartis2012-12-14Not applicableUs
SigniforSolution0.9 mgSubcutaneousNovartis2013-11-28Not applicableCanada
SigniforInjection, solution0.3 mgSubcutaneousNovartis Europharm Limited2012-04-24Not applicableEu
Categories
UNII
98H1T17066
CAS number
396091-73-9
Weight
Average: 1047.2062
Monoisotopic: 1046.50142376
Chemical Formula
C58H66N10O9
InChI Key
VMZMNAABQBOLAK-DBILLSOUSA-N
InChI
InChI=1S/C58H66N10O9/c59-27-13-12-22-46-52(69)64-47(30-38-23-25-42(26-24-38)76-36-39-16-6-2-7-17-39)53(70)66-49(31-37-14-4-1-5-15-37)57(74)68-35-43(77-58(75)61-29-28-60)33-50(68)55(72)67-51(40-18-8-3-9-19-40)56(73)65-48(54(71)63-46)32-41-34-62-45-21-11-10-20-44(41)45/h1-11,14-21,23-26,34,43,46-51,62H,12-13,22,27-33,35-36,59-60H2,(H,61,75)(H,63,71)(H,64,69)(H,65,73)(H,66,70)(H,67,72)/t43-,46+,47+,48-,49+,50+,51+/m1/s1
IUPAC Name
(3S,6R,9S,12S,15S,19R,20aS)-9-(4-aminobutyl)-15-benzyl-12-{[4-(benzyloxy)phenyl]methyl}-6-(1H-indol-3-ylmethyl)-1,4,7,10,13,16-hexaoxo-3-phenyl-icosahydropyrrolo[1,2-a]1,4,7,10,13,16-hexaazacyclooctadecan-19-yl N-(2-aminoethyl)carbamate
SMILES
NCCCC[[email protected]@H]1NC(=O)[[email protected]@H](CC2=CNC3=C2C=CC=C3)NC(=O)[[email protected]@H](NC(=O)[[email protected]@H]2C[[email protected]](CN2C(=O)[[email protected]](CC2=CC=CC=C2)NC(=O)[[email protected]](CC2=CC=C(OCC3=CC=CC=C3)C=C2)NC1=O)OC(=O)NCCN)C1=CC=CC=C1

Pharmacology

Indication

For the treatment of Cushing’s disease, specifically for those patients whom pituitary surgery has not been curative or is not an option.

Structured Indications
Pharmacodynamics

Signifor® is an analogue of somatostatin that promotes reduced levels of cortisol secretion in Cushing's disease patients.

Mechanism of action

Pasireotide activates a broad spectrum of somatostatin receptors, exhbiting a much higher binding affinity for somatostatin receptors 1, 3, and 5 than octreotide in vitro, as well as a comparable binding affinity for somatostatin receptor 2. The binding and activation of the somatostatin receptors causes inhibition of ACTH secretion and results in reduced cortisol secretion in Cushing's disease patients. Also this agent is more potent than somatostatin in inhibiting the release of human growth hormone (HGH), glucagon, and insulin.

TargetActionsOrganism
USomatostatin receptor type 1Not AvailableHuman
USomatostatin receptor type 2Not AvailableHuman
USomatostatin receptor type 3Not AvailableHuman
USomatostatin receptor type 5Not AvailableHuman
Absorption

The peak plasma concentration of pasireotide occurs in 0.25-0.5 hours. After administration of single and multiple doses, there is dose-proportionoal increases in Cmax and AUC.

Volume of distribution

Pasireotide is widely distributed and has a volume of distribution of >100L.

Protein binding

Plasma protein binding is 88%.

Metabolism

Metabolism is minimal.

Route of elimination

Pasireotide is eliminated mostly by hepatic clearance (biliary excretion)(about 48%) with some minor renal clearance (about 7.63%).

Half life

The half-life is 12 hours.

Clearance

The clearance in healthy patient is ~7.6 L/h and in Cushing’s disease patients is ~3.8 L/h.

Toxicity

The most common toxic effects observed are hyperglycemia, cholelithiasis, diarrhea, nausea, headache, abdominal pain, fatigue, and diabetes mellitus.

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

Interactions

Drug Interactions
DrugInteractionDrug group
BromocriptineThe serum concentration of Bromocriptine can be increased when it is combined with Pasireotide.Approved, Investigational
CodeineThe metabolism of Codeine can be decreased when combined with Pasireotide.Approved, Illicit
CyclosporineThe serum concentration of Cyclosporine can be decreased when it is combined with Pasireotide.Approved, Investigational, Vet Approved
Dotatate gallium Ga-68The therapeutic efficacy of Dotatate gallium Ga-68 can be decreased when used in combination with Pasireotide.Approved, Investigational
PegvisomantThe risk or severity of adverse effects can be increased when Pasireotide is combined with Pegvisomant.Approved
Food Interactions
  • Since Signifor® is administered subcutaneously, food has no effect.

References

Synthesis Reference

Bruns C, Lewis I, Briner U, Meno-Tetang G, Weckbecker G: SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur J Endocrinol. 2002 May;146(5):707-16.

General References
  1. Weckbecker G, Briner U, Lewis I, Bruns C: SOM230: a new somatostatin peptidomimetic with potent inhibitory effects on the growth hormone/insulin-like growth factor-I axis in rats, primates, and dogs. Endocrinology. 2002 Oct;143(10):4123-30. [PubMed:12239124]
External Links
KEGG Drug
D10147
PubChem Compound
9941444
PubChem Substance
175427082
ChemSpider
8117062
ChEBI
72312
ChEMBL
CHEMBL3349607
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Pasireotide
ATC Codes
H01CB05 — Pasireotide
AHFS Codes
  • 68:29.04 — Somatostatin Agonists
FDA label
Download (567 KB)
MSDS
Download (567 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentNeuroendocrine Tumors2
1CompletedNot AvailableAlcoholism / Hepatic Cirrhosis1
1CompletedTreatmentAcromegaly / Carcinoid Tumors1
1CompletedTreatmentCarcinoid Tumors / Neuroendocrine Tumors / Progressive Neuroendocrine Tumors of pancreatic origin1
1CompletedTreatmentImpaired Renal Function1
1CompletedTreatmentMalignant Neoplasm of Pancreas1
1CompletedTreatmentNeuroendocrine Tumors1
1, 2Active Not RecruitingTreatmentAdenocarcinoma of the Prostate / Hormone-Resistant Prostate Cancer / Recurrent Prostate Cancer / Stage IV Prostate Cancer1
1, 2Active Not RecruitingTreatmentCastration Resistant Prostate Cancer (CRPC)1
2Active Not RecruitingTreatmentAutosomal Dominant Polycystic Kidney Disease (ADPKD) / Autosomal Dominant Polycystic Liver Disease / Polycystic Liver Disease (PLD) / Somatostatin Analogs1
2Active Not RecruitingTreatmentCarcinoid Tumors / Neuroendocrine Tumors1
2Active Not RecruitingTreatmentThyroid Cancers1
2CompletedPreventionCancer, Breast1
2CompletedTreatmentAcromegaly1
2CompletedTreatmentAdvanced Adult Hepatocellular Carcinoma1
2CompletedTreatmentAngiodysplasia1
2CompletedTreatmentCarcinoid Tumors1
2CompletedTreatmentCushing's Disease1
2CompletedTreatmentDumping Syndrome Patients1
2CompletedTreatmentHepatocellular,Carcinoma1
2CompletedTreatmentHyperglycemias1
2CompletedTreatmentLocal Recurrent Thymoma / Primary Inoperable Thymoma1
2CompletedTreatmentPostoperative Dumping Syndrome1
2Not Yet RecruitingTreatmentCongenital Hyperinsulinism / Hyperinsulinism / Insulinoma1
2Not Yet RecruitingTreatmentEnterostomy1
2RecruitingTreatmentACTH-producing pituitary tumour / Pituitary Neoplasms1
2RecruitingTreatmentCluster Headache - Episodic and Chronic1
2RecruitingTreatmentEctopic Corticotropin Syndrome1
2RecruitingTreatmentHaematological Malignancies1
2TerminatedTreatmentCancers1
2TerminatedTreatmentCastrate Resistant Prostate Cancer (CRPC) / Chemotherapy Naive Prostate Cancer / Prostate Cancer1
2TerminatedTreatmentEctopic Corticotropin Syndrome / Nelson Syndrome / Neoplasms, Pancreatic / Pituitary Neoplasms1
2TerminatedTreatmentGonadotroph Adenomas1
2TerminatedTreatmentNelson Syndrome1
2Unknown StatusTreatmentLung Cancer Small Cell Lung Cancer (SCLC)1
2WithdrawnTreatmentMultiple Myeloma (MM)1
2WithdrawnTreatmentMultiple Myeloma (MM) / Multiple Myeloma in Relapse1
2, 3CompletedTreatmentNon-functioning Pituitary Adenomas / Prolactinomas1
3Active Not RecruitingTreatmentAcromegaly2
3CompletedTreatmentAcromegaly1
3CompletedTreatmentCushing's Disease1
3CompletedTreatmentMalignant Neoplasm of Pancreas1
3CompletedTreatmentSymptomatic Refractory Resistant Carcinoid Disease1
4Active Not RecruitingTreatmentAcromegaly1
4CompletedTreatmentCushing's Disease1
4Enrolling by InvitationTreatmentBMI >30 kg/m2 / General Surgery / Hypoglycemia1
4RecruitingPreventionNeoplasms, Pancreatic / Pancreatic Fistula1
4RecruitingTreatmentAcromegaly / Cushing's Disease / Dumping Syndrome / Ectopic ACTH Secreting (EAS) Tumors / Melanoma Negative for bRAF / Melanoma Negative for nRAS / Neuroendocrine Tumors / Pituitary Neoplasms / Prostate Cancer1
4WithdrawnTreatmentGastro-enteropancreatic Neuroendocrine Tumor1
Not AvailableAvailableNot AvailableCongenital Hyperinsulinism1
Not AvailableRecruitingNot AvailableCushings Disease1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
InjectionSubcutaneous.3 mg/mL
InjectionSubcutaneous.6 mg/mL
InjectionSubcutaneous.9 mg/mL
Injection, powder, for suspensionIntramuscular20 mg
Injection, powder, for suspensionIntramuscular40 mg
Injection, powder, for suspensionIntramuscular60 mg
Injection, solutionSubcutaneous0.3 mg
Injection, solutionSubcutaneous0.6 mg
Injection, solutionSubcutaneous0.9 mg
SolutionSubcutaneous0.3 mg
SolutionSubcutaneous0.6 mg
SolutionSubcutaneous0.9 mg
Kit
Kit; powder, for suspensionIntramuscular20 mg
Kit; powder, for suspensionIntramuscular40 mg
Kit; powder, for suspensionIntramuscular60 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6225284No1996-06-282016-06-28Us
US7473761No2005-07-292025-07-29Us
US8299209No2005-12-272025-12-27Us
US8822637No2003-08-062023-08-06Us
US7759308No2006-10-252026-10-25Us
US9351923No2008-05-232028-05-23Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilitySoluble in water.From The Merck Index.
Predicted Properties
PropertyValueSource
Water Solubility0.00203 mg/mLALOGPS
logP3.03ALOGPS
logP2.68ChemAxon
logS-5.7ALOGPS
pKa (Strongest Acidic)9.09ChemAxon
pKa (Strongest Basic)10.43ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count9ChemAxon
Polar Surface Area281.2 Å2ChemAxon
Rotatable Bond Count18ChemAxon
Refractivity286.66 m3·mol-1ChemAxon
Polarizability111.29 Å3ChemAxon
Number of Rings8ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9926
Blood Brain Barrier-0.5389
Caco-2 permeable-0.8325
P-glycoprotein substrateSubstrate0.656
P-glycoprotein inhibitor INon-inhibitor0.6717
P-glycoprotein inhibitor IINon-inhibitor0.6843
Renal organic cation transporterNon-inhibitor0.777
CYP450 2C9 substrateNon-substrate0.8878
CYP450 2D6 substrateNon-substrate0.758
CYP450 3A4 substrateSubstrate0.521
CYP450 1A2 substrateNon-inhibitor0.7641
CYP450 2C9 inhibitorNon-inhibitor0.7676
CYP450 2D6 inhibitorNon-inhibitor0.8704
CYP450 2C19 inhibitorInhibitor0.5307
CYP450 3A4 inhibitorInhibitor0.575
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6561
Ames testNon AMES toxic0.7722
CarcinogenicityNon-carcinogens0.8568
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.4609 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8711
hERG inhibition (predictor II)Inhibitor0.7476
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

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
Cyclic peptides / Macrolactams / 3-alkylindoles / Alpha amino acids and derivatives / Phenol ethers / Phenoxy compounds / Alkyl aryl ethers / Substituted pyrroles / Pyrrolidines / Heteroaromatic compounds
show 11 more
Substituents
Alpha-oligopeptide / Cyclic alpha peptide / Macrolactam / Alpha-amino acid or derivatives / 3-alkylindole / Indole or derivatives / Indole / Phenoxy compound / Phenol ether / Alkyl aryl ether
show 28 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
homodetic cyclic peptide, peptide hormone (CHEBI:72312)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Somatostatin receptor activity
Specific Function
Receptor for somatostatin with higher affinity for somatostatin-14 than -28. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase. In addition it stim...
Gene Name
SSTR1
Uniprot ID
P30872
Uniprot Name
Somatostatin receptor type 1
Molecular Weight
42685.77 Da
References
  1. Zatelli MC, Piccin D, Vignali C, Tagliati F, Ambrosio MR, Bondanelli M, Cimino V, Bianchi A, Schmid HA, Scanarini M, Pontecorvi A, De Marinis L, Maira G, degli Uberti EC: Pasireotide, a multiple somatostatin receptor subtypes ligand, reduces cell viability in non-functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion. Endocr Relat Cancer. 2007 Mar;14(1):91-102. [PubMed:17395978]
  2. Bruns C, Lewis I, Briner U, Meno-Tetang G, Weckbecker G: SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur J Endocrinol. 2002 May;146(5):707-16. [PubMed:11980628]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Somatostatin receptor activity
Specific Function
Receptor for somatostatin-14 and -28. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase. In addition it stimulates phosphotyrosine phosphatase and ...
Gene Name
SSTR2
Uniprot ID
P30874
Uniprot Name
Somatostatin receptor type 2
Molecular Weight
41332.37 Da
References
  1. Zatelli MC, Piccin D, Vignali C, Tagliati F, Ambrosio MR, Bondanelli M, Cimino V, Bianchi A, Schmid HA, Scanarini M, Pontecorvi A, De Marinis L, Maira G, degli Uberti EC: Pasireotide, a multiple somatostatin receptor subtypes ligand, reduces cell viability in non-functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion. Endocr Relat Cancer. 2007 Mar;14(1):91-102. [PubMed:17395978]
  2. Bruns C, Lewis I, Briner U, Meno-Tetang G, Weckbecker G: SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur J Endocrinol. 2002 May;146(5):707-16. [PubMed:11980628]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Somatostatin receptor activity
Specific Function
Receptor for somatostatin-14 and -28. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase.
Gene Name
SSTR3
Uniprot ID
P32745
Uniprot Name
Somatostatin receptor type 3
Molecular Weight
45846.995 Da
References
  1. Zatelli MC, Piccin D, Vignali C, Tagliati F, Ambrosio MR, Bondanelli M, Cimino V, Bianchi A, Schmid HA, Scanarini M, Pontecorvi A, De Marinis L, Maira G, degli Uberti EC: Pasireotide, a multiple somatostatin receptor subtypes ligand, reduces cell viability in non-functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion. Endocr Relat Cancer. 2007 Mar;14(1):91-102. [PubMed:17395978]
  2. Bruns C, Lewis I, Briner U, Meno-Tetang G, Weckbecker G: SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur J Endocrinol. 2002 May;146(5):707-16. [PubMed:11980628]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Somatostatin receptor activity
Specific Function
Receptor for somatostatin 28 and to a lesser extent for somatostatin-14. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase. Increases cell growth inhibition act...
Gene Name
SSTR5
Uniprot ID
P35346
Uniprot Name
Somatostatin receptor type 5
Molecular Weight
39201.925 Da
References
  1. Zatelli MC, Piccin D, Vignali C, Tagliati F, Ambrosio MR, Bondanelli M, Cimino V, Bianchi A, Schmid HA, Scanarini M, Pontecorvi A, De Marinis L, Maira G, degli Uberti EC: Pasireotide, a multiple somatostatin receptor subtypes ligand, reduces cell viability in non-functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion. Endocr Relat Cancer. 2007 Mar;14(1):91-102. [PubMed:17395978]
  2. Bruns C, Lewis I, Briner U, Meno-Tetang G, Weckbecker G: SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur J Endocrinol. 2002 May;146(5):707-16. [PubMed:11980628]

Drug created on March 19, 2008 10:46 / Updated on January 15, 2018 08:56