Lutetium Lu 177 dotatate

Identification

Name
Lutetium Lu 177 dotatate
Accession Number
DB13985
Description

A 177Lu-labeled somatostatin analog peptide, Lutetium Lu 177 dotatate belongs to an emerging form of treatments called Peptide Receptor Radionuclide Therapy (PRRT), which involves targeting tumours with molecules carrying radioactive particles that bind to specific receptors expressed by the tumour. Lutetium Lu 177 dotatate may also be referred to as 177Lu-DOTA-Tyr3-octreotate. Compared to the alternative somatostatin analogue DOTA-Tyr3-octreotide (dotatoc), Lutetium Lu 177 dotatate displays higher uptake of radioactivity in tumors and better residence times 1. In terms of biodistribution, Lutetium Lu 177 dotatate demonstrated a lower whole-body retention, indicating potentially lower risk for bone marrow toxicity 1. The presence of a radioligand allows monitoring of treatment response post therapy and prior to next fraction of the dose delivery which may be clinically beneficial in estimating the intensity of lesion uptakes or deciding the dose for subsequent administrations 3.

Lutetium Lu 177 dotatate was approved by the FDA as Lutathera in January 2018 for intravenous injection. It is a first radiopharmaceutical agent to be approved for gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and is indicated for adult patients with somatostatin receptor-positive GEP-NETs 7. Targeting pancreas and other parts of the gastrointestinal tract such as the intestines and colon, neuroendocrine tumors may commonly metastasize to metastasize to the mesentery, peritoneum, and liver 2. Patients with GEP-NETs have limited second-line treatment options after the metastasis of tumors and inadequate therapeutic response from first-line therapies. In a clinical trial involving patients with advanced somatostatin receptor-positive GEP-NET, the treatment of Lutetium Lu 177 dotatate in combination with octreotide resulted in longer progression-free survival compared to patients receiving octreotide alone and there was evidence of an overall survival benefit 2.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 1609.55
Monoisotopic: 1608.515088972
Chemical Formula
C65H87LuN14O19S2
Synonyms
  • 177Lu-DOTA-octreotate
  • 177Lu-DOTA-Tyr3-octreotate
  • 177Lu-dotatate
  • Dotatate lutenium Lu-177
  • Lu-DOTA-TATE
  • Lutetium dotatate Lu-177
  • lutetium Lu 177 dotatate
  • Lutetium oxodotreotide Lu-177

Pharmacology

Indication

Indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults Label.

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Clinically significant myelosuppression occurred in less than 10% of patients in the Lutetium Lu 177 dotatate (177Lu-Dotatate) group in one clinical trial 2. According to an open label study involving 20 patients with somatostatin receptor-positive midgut carcinoid tumors, the treatment with did not result in any large changes in the mean QTc interval (i.e., >20 ms) Label. Due to high expression of SSTR2, pancreas was the primary target in animal studies using a non-radioactive form of lutetium Lu 177 dotatate (lutetium Lu 175 dotatate) Label.

Mechanism of action

Somatostatin receptors (SSRT) are inhibitory G-protein coupled receptors that are ubiquitously expressed in normal and cancer cells. The natural ligand of SSRTs, somatostatin, is a potent inhibitory regulator of pituitary and gastrointestinal hormone release and proliferation 4. Advanced and well-differentiated neuroendocrine tumors express high levels of somatostatin receptors, especially somatostatin recetor type 2 (SSRT2), 5 and have the ability to incorporate amines intracellularly and decarboxylate them 6.

As an analogue of somatostatin, Lutetium Lu 177 dotatate binds to somatostatin receptor with highest binding affinity for SSRT2. Upon binding to SSRT-expressing cells, including malignant somatostatin receptor-positive tumors, the radiolabelled compound is internalized and the beta emission from the radioligand Lu 177 induces cellular damage by formation of free radicals in somatostatin receptor-positive cells and in neighboring cells Label,4. As with other somatostatin analogues, Lu177 dotatate is expected to suppress excessive secretion of amines and hormones, such as serotonin, from carcinoid tumors and certain types of endocrine pancreatic tumors (glucagonoma, VIPoma and gastrinoma) 5. The release of peptides and other gastrointestinal hormones important in tumor growth, including gastrin, cholecystokinin and epidermal growth factor (EGF), may also be reduced through promoted somtatostatin signalling pathways.

TargetActionsOrganism
ASomatostatin receptor type 2
agonist
Humans
ASomatostatin receptor type 1
agonist
Humans
ASomatostatin receptor type 3
agonist
Humans
ASomatostatin receptor type 4
agonist
Humans
ASomatostatin receptor type 5
agonist
Humans
Absorption

At the recommended intravenous dose, the mean blood exposure (AUC) of lutetium Lu 177 dotatate was 41 ng.h/mL (coefficient of variation, or CV, 36 %). The mean maximum plasma concentration (Cmax) was 10 ng/mL (CV 50%) and was observed at the end of the intravenous infusion of lutetium Lu 177 dotatate Label.

Volume of distribution

The mean volume of distribution is 460 L (CV 54%). Within 4 hours of administration, distribution in kidneys, tumor lesions, liver, spleen, and, in some patients, pituitary gland and thyroid was observed. High uptake of the radiolabeled peptide in the pancreas in animal biodistribution studies was observed due to high expression of SSTR2 Label. Co-administration of amino acids with lutetium Lu 177 dotatate may decrease the extent of drug distribution to the kidneys.

Protein binding

The non-radioactive form of lutetium dotatate is 43% bound to human plasma proteins Label.

Metabolism

Lutetium Lu 177 dotatate does not undergo hepatic metabolism Label.

Route of elimination

Lutetium Lu 177 dotatate predominantly undergoes renal excretion with cumulative excretion of 44% within 5 hours, 58% within 24 hours, and 65% within 48 hours following intravenous administration. Greater than 99% of total administered dose is expected to be eliminated within 14 days after administration although prolonged renal elimination is expected Label.

Half-life

The mean (± standard deviation) effective blood elimination half-life is 3.5 (±1.4) hours and the mean terminal blood half-life is 71 (± 28) hours Label.

Clearance

The mean clearance (CL) is 4.5 L/h (CV 31%). Co-administration of amino acids with lutetium Lu 177 dotatate increased the mean beta-phase blood clearance of lutetium Lu 177 dotatate by 36% Label.

Adverse Effects
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Toxicity

While carcinogenicity and mutagenicity studies have not been conducted with lutetium 177 dotatate, radioisotope is considered a carcinogen and mutagen. No fertility studies have been performed Label. In repeat dose toxicity studies of rats, pancreatic acinar apoptosis occurred at lutetium Lu 175 dotatate doses ≥ 5 mg/kg. Pancreatic acinar cell atrophy also occurred in repeat dose toxicology studies in dogs at doses ≥ 500 mg/kg Label.

Affected organisms
  • Humans and other mammals
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
LanreotideThe therapeutic efficacy of Lutetium Lu 177 dotatate can be decreased when used in combination with Lanreotide.
OctreotideThe therapeutic efficacy of Lutetium Lu 177 dotatate can be decreased when used in combination with Octreotide.
PasireotideThe therapeutic efficacy of Lutetium Lu 177 dotatate can be decreased when used in combination with Pasireotide.
SomatostatinThe therapeutic efficacy of Lutetium Lu 177 dotatate can be decreased when used in combination with Somatostatin.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

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  • Evidence Level
    Evidence Level

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  • Action
    Action

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Food Interactions
No interactions found.

Products

Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
LutatheraInjection10 mCi/1mLIntravenousAdvanced Accelerator Applications Usa, Inc2018-01-26Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

Drug Categories
Classification
Not classified

Chemical Identifiers

UNII
AE221IM3BB
CAS number
437608-50-9
InChI Key
MXDPZUIOZWKRAA-PRDSJKGBSA-K
InChI
InChI=1S/C65H90N14O19S2.Lu/c1-38(80)56-64(96)73-51(63(95)75-57(39(2)81)65(97)98)37-100-99-36-50(72-59(91)47(28-40-10-4-3-5-11-40)68-52(83)32-76-20-22-77(33-53(84)85)24-26-79(35-55(88)89)27-25-78(23-21-76)34-54(86)87)62(94)70-48(29-41-15-17-43(82)18-16-41)60(92)71-49(30-42-31-67-45-13-7-6-12-44(42)45)61(93)69-46(58(90)74-56)14-8-9-19-66;/h3-7,10-13,15-18,31,38-39,46-51,56-57,67,80-82H,8-9,14,19-30,32-37,66H2,1-2H3,(H,68,83)(H,69,93)(H,70,94)(H,71,92)(H,72,91)(H,73,96)(H,74,90)(H,75,95)(H,84,85)(H,86,87)(H,88,89)(H,97,98);/q;+3/p-3/t38-,39-,46+,47-,48+,49-,50+,51+,56+,57+;/m1./s1/i;1+2
IUPAC Name
(177Lu)lutetium(3+) 2-[4-({[(1R)-1-{[(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-4-{[(1S,2R)-1-carboxy-2-hydroxypropyl]carbamoyl}-7-[(1R)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-[(1H-indol-3-yl)methyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentaazacycloicosan-19-yl]carbamoyl}-2-phenylethyl]carbamoyl}methyl)-7,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetate
SMILES
[177Lu+3].C[[email protected]@H](O)[[email protected]](NC(=O)[[email protected]@H]1CSSC[[email protected]](NC(=O)[[email protected]@H](CC2=CC=CC=C2)NC(=O)CN2CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC2)C(=O)N[[email protected]@H](CC2=CC=C(O)C=C2)C(=O)N[[email protected]](CC2=CNC3=C2C=CC=C3)C(=O)N[[email protected]@H](CCCCN)C(=O)N[[email protected]@H]([[email protected]@H](C)O)C(=O)N1)C(O)=O

References

General References
  1. Kam BL, Teunissen JJ, Krenning EP, de Herder WW, Khan S, van Vliet EI, Kwekkeboom DJ: Lutetium-labelled peptides for therapy of neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2012 Feb;39 Suppl 1:S103-12. doi: 10.1007/s00259-011-2039-y. [PubMed:22388631]
  2. Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Oberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E: Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. doi: 10.1056/NEJMoa1607427. [PubMed:28076709]
  3. Singh N, Krishna B, Vyas M, Venkatesh M, Banerjee S, Das T, Nair KV, Sudipta: Lutetium DOTATATE whole body scans: A novel approach for evaluation of neuroendocrine tumors. Indian J Nucl Med. 2011 Jul;26(3):135-8. doi: 10.4103/0972-3919.103994. [PubMed:23326064]
  4. Zou Y, Xiao X, Li Y, Zhou T: Somatostatin analogues inhibit cancer cell proliferation in an SSTR2-dependent manner via both cytostatic and cytotoxic pathways. Oncol Rep. 2009 Feb;21(2):379-86. [PubMed:19148511]
  5. Wangberg B, Nilsson O, Johanson V V, Kolby L, Forssell-Aronsson E, Andersson P, Fjalling M, Tisell L, Ahlman H: Somatostatin Receptors in the Diagnosis and Therapy of Neuroendocrine Tumor. Oncologist. 1997;2(1):50-58. [PubMed:10388029]
  6. Kvols LK, Reubi JC, Horisberger U, Moertel CG, Rubin J, Charboneau JW: The presence of somatostatin receptors in malignant neuroendocrine tumor tissue predicts responsiveness to octreotide. Yale J Biol Med. 1992 Sep-Oct;65(5):505-18; discussion 531-6. [PubMed:1364090]
  7. FDA Press Announcements: FDA approves new treatment for certain digestive tract cancers [Link]
ChemSpider
32699095
RxNav
1999335
FDA label
Download (844 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentCarcinoid Tumor of the Small Bowel / Neuroendocrine Tumours1
3RecruitingTreatmentGastro-enteropancreatic Neuroendocrine Tumor1
3RecruitingTreatmentGastroenteropancreatic Neuroendocrine Tumors1
3WithdrawnTreatmentGastro-intestinal Neuroendocrine Tumors1
2Active Not RecruitingTreatmentNeuroendocrine Tumors2
2Not Yet RecruitingTreatmentAnatomic Stage IV Breast Cancer AJCC v8 / Metastatic Breast Carcinoma / Prognostic Stage IV Breast Cancer AJCC v8 / Recurrent Breast Carcinoma1
2Not Yet RecruitingTreatmentCarcinoid Heart Disease / Carcinoid Syndrome / Carcinoid Tumors1
2RecruitingTreatmentCarcinoid Tumors / Neuroendocrine Carcinomas / Neuroendocrine Tumors1
2RecruitingTreatmentGrade I Meningioma / Grade II Meningioma / Grade III Meningioma / Recurrent Meningiomas / Unresectable Meningioma1
2RecruitingTreatmentMeningiomas1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntravenous10 mCi/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US10596276No2018-07-252038-07-25Us
US10596278No2018-07-252038-07-25Us
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.193 mg/mLALOGPS
logP-0.78ALOGPS
logP-8.4ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)0.47ChemAxon
pKa (Strongest Basic)10.28ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count24ChemAxon
Hydrogen Donor Count14ChemAxon
Polar Surface Area505.95 Å2ChemAxon
Rotatable Bond Count26ChemAxon
Refractivity397.34 m3·mol-1ChemAxon
Polarizability144.31 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
Curator comments
Half-maximal inhibitory concentration (SEM) of 1.5 (0.4) nM for non-radiolabelled chelator DOTA-[Tyr3]octreotate (dotatate).
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. Kam BL, Teunissen JJ, Krenning EP, de Herder WW, Khan S, van Vliet EI, Kwekkeboom DJ: Lutetium-labelled peptides for therapy of neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2012 Feb;39 Suppl 1:S103-12. doi: 10.1007/s00259-011-2039-y. [PubMed:22388631]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
Curator comments
Half-maximal inhibitory concentration (SEM) of >10,000 nM for non-radiolabelled chelator DOTA-[Tyr3]octreotate (dotatate).
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. Kam BL, Teunissen JJ, Krenning EP, de Herder WW, Khan S, van Vliet EI, Kwekkeboom DJ: Lutetium-labelled peptides for therapy of neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2012 Feb;39 Suppl 1:S103-12. doi: 10.1007/s00259-011-2039-y. [PubMed:22388631]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
Curator comments
Half-maximal inhibitory concentration (SEM) of >1,000 nM for non-radiolabelled chelator DOTA-[Tyr3]octreotate (dotatate).
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. Kam BL, Teunissen JJ, Krenning EP, de Herder WW, Khan S, van Vliet EI, Kwekkeboom DJ: Lutetium-labelled peptides for therapy of neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2012 Feb;39 Suppl 1:S103-12. doi: 10.1007/s00259-011-2039-y. [PubMed:22388631]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
Curator comments
Half-maximal inhibitory concentration (SEM) of 453 (176) nM for non-radiolabelled chelator DOTA-[Tyr3]octreotate (dotatate).
General Function
Receptor for somatostatin-14. The activity of this receptor is mediated by G proteins which inhibits adenylyl cyclase. It is functionally coupled not only to inhibition of adenylate cyclase, but also to activation of both arachidonate release and mitogen-activated protein (MAP) kinase cascade. Mediates antiproliferative action of somatostatin in tumor cells.
Specific Function
Neuropeptide binding
Gene Name
SSTR4
Uniprot ID
P31391
Uniprot Name
Somatostatin receptor type 4
Molecular Weight
42002.245 Da
References
  1. Kam BL, Teunissen JJ, Krenning EP, de Herder WW, Khan S, van Vliet EI, Kwekkeboom DJ: Lutetium-labelled peptides for therapy of neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2012 Feb;39 Suppl 1:S103-12. doi: 10.1007/s00259-011-2039-y. [PubMed:22388631]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
Curator comments
Half-maximal inhibitory concentration (SEM) of 547 (160) nM for non-radiolabelled chelator DOTA-[Tyr3]octreotate (dotatate).
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. Kam BL, Teunissen JJ, Krenning EP, de Herder WW, Khan S, van Vliet EI, Kwekkeboom DJ: Lutetium-labelled peptides for therapy of neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2012 Feb;39 Suppl 1:S103-12. doi: 10.1007/s00259-011-2039-y. [PubMed:22388631]

Drug created on January 26, 2018 16:01 / Updated on June 12, 2020 11:42

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