Identification
- Summary
Lutetium Lu 177 dotatate is a radiolabeled somatostatin analog used to treat somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors.
- Brand Names
- Lutathera
- Generic Name
- Lutetium Lu 177 dotatate
- DrugBank Accession Number
- DB13985
- Background
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
Structure for Lutetium Lu 177 dotatate (DB13985)
- 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 8.
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- Contraindications & Blackbox Warnings
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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).8 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) 8.
- 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 8,4. 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.
Target Actions Organism ASomatostatin receptor type 2 agonistHumans ASomatostatin receptor type 1 agonistHumans ASomatostatin receptor type 3 agonistHumans ASomatostatin receptor type 4 agonistHumans ASomatostatin receptor type 5 agonistHumans - 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 8.
- 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 8. 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 8.
- Metabolism
Lutetium Lu 177 dotatate does not undergo hepatic metabolism 8.
- 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 8.
- 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 8.
- 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% 8.
- Adverse Effects
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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 8.
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareLanreotide The therapeutic efficacy of Lutetium Lu 177 dotatate can be decreased when used in combination with Lanreotide. Octreotide The therapeutic efficacy of Lutetium Lu 177 dotatate can be decreased when used in combination with Octreotide. Pasireotide The therapeutic efficacy of Lutetium Lu 177 dotatate can be decreased when used in combination with Pasireotide. Somatostatin The therapeutic efficacy of Lutetium Lu 177 dotatate can be decreased when used in combination with Somatostatin. 
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- No interactions found.
Products
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Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Lutathera Injection, solution 370 MBq/ml Intravenous Advanced Accelerator Applications 2020-12-16 Not applicable EU 
Lutathera Injection 10 mCi/1mL Intravenous Advanced Accelerator Applications Usa, Inc 2018-01-26 Not applicable US 
Categories
- Drug Categories
- Classification
- Not classified
- Affected organisms
- Humans and other mammals
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[C@@H](O)[C@H](NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H](CC2=CC=CC=C2)NC(=O)CN2CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC2)C(=O)N[C@@H](CC2=CC=C(O)C=C2)C(=O)N[C@H](CC2=CNC3=C2C=CC=C3)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1)C(O)=O
References
- General References
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- FDA Press Announcements: FDA approves new treatment for certain digestive tract cancers [Link]
- FDA Approved Drug Products: LUTATHERA (lutetium Lu 177 dotatate) injection for intravenous use [Link]
- External Links
Clinical Trials
- Clinical Trials
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection Intravenous 10 mCi/1mL Solution Intravenous 370 MBq/ml Injection, solution Intravenous 370 Mbq/ml - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US10596276 No 2020-03-24 2038-07-25 US US10596278 No 2020-03-24 2038-07-25 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.193 mg/mL ALOGPS logP -0.78 ALOGPS logP -8.4 Chemaxon logS -4 ALOGPS pKa (Strongest Acidic) 0.47 Chemaxon pKa (Strongest Basic) 10.28 Chemaxon Physiological Charge -2 Chemaxon Hydrogen Acceptor Count 24 Chemaxon Hydrogen Donor Count 14 Chemaxon Polar Surface Area 505.95 Å2 Chemaxon Rotatable Bond Count 26 Chemaxon Refractivity 397.34 m3·mol-1 Chemaxon Polarizability 144.31 Å3 Chemaxon Number of Rings 6 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - 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
- 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. [Article]
- 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
- 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. [Article]
- 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
- 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. [Article]
- 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
- 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. [Article]
- 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
- 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. [Article]
Drug created at January 26, 2018 23:01 / Updated at July 02, 2022 12:49