Lutetium (177Lu) oxodotreotide

Last updated
Lutetium (177Lu) dotatate
INN: lutetium (177Lu) oxodotreotide
Lutetium (177Lu) oxodotreotide.svg
Clinical data
Trade names Lutathera
AHFS/Drugs.com Monograph
License data
Routes of
administration 		Intravenous
Drug class Antineoplastic agent
ATC code
Legal status
Legal status
  • CA:Rx-only / Schedule C [1]
  • UK: POM (Prescription only) [2]
  • US: ℞-only [3]
  • EU:Rx-only [4]
  • In general: ℞ (Prescription only)
Identifiers
  • (177Lu)lutetium(3+) 2-[4-({[(1R)-1-{[(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-4-{[(1S,2R)-1-carboxy-2-hydroxypropyl]-C-hydroxycarbonimidoyl}-6,9,12,15,18-pentahydroxy-7-[(1R)-1-hydroxyethyl]-13-[(1H-indol-3-yl)methyl]-16-[(4-oxidophenyl)methyl]-1,2-dithia-5,8,11,14,17-pentaazacycloicosa-5,8,11,14,17-pentaen-19-yl]-C-hydroxycarbonimidoyl}-2-phenylethyl]-C-hydroxycarbonimidoyl}methyl)-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetate
CAS Number
PubChem CID
DrugBank
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
Formula C65H87LuN14O19S2
Molar mass 1607.58 g·mol−1
3D model (JSmol)
  • CC(C1C(=O)NC(CSSCC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N1)CCCCN)CC2=CNC3=CC=CC=C32)CC4=CC=C(C=C4)O)NC(=O)C(CC5=CC=CC=C5)NC(=O)CN6CCN(CCN(CCN(CC6)CC(=O)[O-])CC(=O)[O-])CC(=O)[O-])C(=O)NC(C(C)O)C(=O)O)O.[Lu+3]
  • 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
  • Key:MXDPZUIOZWKRAA-PRDSJKGBSA-K

Lutetium (177Lu) oxodotreotide (INN) or 177Lu DOTA-TATE, trade name Lutathera, is a chelated complex of a radioisotope of the element lutetium with DOTA-TATE, used in peptide receptor radionuclide therapy (PRRT). Specifically, it is used in the treatment of cancers which express somatostatin receptors. [5]

Contents

Alternatives to 177Lu-DOTATE include yttrium-90 DOTATATE or DOTATOC. The longer range of the beta particles emitted by 90Y, which deliver the therapeutic effect, may make it more suitable for large tumors with 177Lu reserved for smaller volumes [6] [7]

The U.S. Food and Drug Administration (FDA) considers 177Lu dotatate to be a first-in-class medication. [8]

Clinical trials and drug approval

The European Commission approved lutetium (177Lu) oxodotreotide (trade name Lutathera) "for the treatment of unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive gastroenteropancreatic neuroendocrine tumours (GEP-NETs) in adults" in September 2017. [9] [4]

177Lu DOTA-TATE was approved in the United States for the treatment of SSTR positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut and hindgut neuroendocrine tumors in adults, in January 2018. [3] [10] [11] This was the first time a radiopharmaceutical had been approved for the treatment of GEP-NETs in the United States. [10]

The U.S. Food and Drug Administration (FDA) approved 177Lu dotatate based primarily on evidence from one clinical trial, NETTER-1 of 229 participants with somatostatin-receptor positive midgut GEP-NETs. [12] Enrolled participants had tumors which could not be surgically removed and were worsening while receiving treatment with octreotide. [12]

Participants were randomly assigned to receive either 177Lu dotatate with long-acting octreotide or long-acting octreotide, at a higher dose, alone. [12] 177Lu dotatate was injected through the vein and long-acting octreotide was injected in the muscle. [12] Both, participants and health care providers knew which treatment was given. [12] The benefit of 177Lu dotatate was evaluated by measuring the length of time that tumors did not grow after treatment and compared it to the control group (progression free survival). [12]

The FDA considered additional data from a second study based on data from 1,214 participants with somatostatin receptor-positive tumors, including GEP-NETS, who received 177Lu dotatate at a single site in the Netherlands, Erasmus MC. [10] [12] All participants received 177Lu dotatate with octreotide. [12] Participants and health care providers knew which treatment was given. [12] The benefit of 177Lu dotatate was evaluated by measuring if and how much the tumor size changed during treatment (the overall response rate). [12] Complete or partial tumor shrinkage was reported in 16 percent of a subset of 360 participants with GEP-NETs who were evaluated for response by the FDA. [10] Participants initially enrolled in the study received 177Lu dotatate as part of an expanded access program. [10]

The FDA granted the application for 177Lu dotatate priority review designation and orphan drug designation. [10] The FDA granted the approval of Lutathera to Advanced Accelerator Applications. [10]

In April 2024, the FDA approved 177Lu dotatate for the treatment of pediatric patients 12 years and older with somatostatin receptor-positive (SSTR+) gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut NETs. [13]

Adverse effects

The therapeutic effect of 177Lu derives from the ionizing beta radiation it emits, however this can also be harmful to healthy tissue and organs. The kidneys are particularly at risk as they help to remove 177Lu DOTA-TATE from the body. [14] To protect them, an amino acid solution (arginine/lysine) is administered by slow infusion, starting before the radioactive administration and normally continuing for several hours afterwards. [7] [15] [16]

Related Research Articles

A radioligand is a microscopic particle which consists of a therapeutic radioactive isotope and the cell-targeting compound - the ligand. The ligand is the target binding site, it may be on the surface of the targeted cancer cell for therapeutic purposes. Radioisotopes can occur naturally or be synthesized and produced in a cyclotron/nuclear reactor. The different types of radioisotopes include Y-90, H-3, C-11, Lu-177, Ac-225, Ra-223, In-111, I-131, I-125, etc. Thus, radioligands must be produced in special nuclear reactors for the radioisotope to remain stable. Radioligands can be used to analyze/characterize receptors, to perform binding assays, to help in diagnostic imaging, and to provide targeted cancer therapy. Radiation is a novel method of treating cancer and is effective in short distances along with being unique/personalizable and causing minimal harm to normal surrounding cells. Furthermore, radioligand binding can provide information about receptor-ligand interactions in vitro and in vivo. Choosing the right radioligand for the desired application is important. The radioligand must be radiochemically pure, stable, and demonstrate a high degree of selectivity, and high affinity for their target.

<span class="mw-page-title-main">Octreotide</span> Octapeptide that mimics natural somatostatin pharmacologically

Octreotide, sold under the brand name Sandostatin among others, is an octapeptide that mimics natural somatostatin pharmacologically, though it is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone. It was first synthesized in 1979 by the chemist Wilfried Bauer, and binds predominantly to the somatostatin receptors SSTR2 and SSTR5.

<span class="mw-page-title-main">Carcinoid</span> Slow-growing type of neuroendocrine tumor

A carcinoid is a slow-growing type of neuroendocrine tumor originating in the cells of the neuroendocrine system. In some cases, metastasis may occur. Carcinoid tumors of the midgut are associated with carcinoid syndrome.

A gallium scan is a type of nuclear medicine test that uses either a gallium-67 (67Ga) or gallium-68 (68Ga) radiopharmaceutical to obtain images of a specific type of tissue, or disease state of tissue. Gallium salts like gallium citrate and gallium nitrate may be used. The form of salt is not important, since it is the freely dissolved gallium ion Ga3+ which is active. Both 67Ga and 68Ga salts have similar uptake mechanisms. Gallium can also be used in other forms, for example 68Ga-PSMA is used for cancer imaging. The gamma emission of gallium-67 is imaged by a gamma camera, while the positron emission of gallium-68 is imaged by positron emission tomography (PET).

<span class="mw-page-title-main">Neuroendocrine tumor</span> Medical condition

Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. They most commonly occur in the intestine, where they are often called carcinoid tumors, but they are also found in the pancreas, lung, and the rest of the body.

<span class="mw-page-title-main">Lanreotide</span> Pharmaceutical drug

Lanreotide, sold under the brand name Somatuline among others, is a medication used in the management of acromegaly and symptoms caused by neuroendocrine tumors, most notably carcinoid syndrome. It is a long-acting analogue of somatostatin, like octreotide.

<span class="mw-page-title-main">Somatostatin receptor 2</span> Protein-coding gene in the species Homo sapiens

Somatostatin receptor type 2 is a protein that in humans is encoded by the SSTR2 gene.

<span class="mw-page-title-main">Octreotide scan</span> Type of medical imaging

An octreotide scan is a type of SPECT scintigraphy used to find carcinoid, pancreatic neuroendocrine tumors, and to localize sarcoidosis. It is also called somatostatin receptor scintigraphy (SRS). Octreotide, a drug similar to somatostatin, is radiolabeled with indium-111, and is injected into a vein and travels through the bloodstream. The radioactive octreotide attaches to tumor cells that have receptors for somatostatin. A gamma camera detects the radioactive octreotide, and makes pictures showing where the tumor cells are in the body, typically by a SPECT technique. A technetium-99m based radiopharmaceutical kit is also available.

Indium-111 (111In) is a radioactive isotope of indium (In). It decays by electron capture to stable cadmium-111 with a half-life of 2.8 days. Indium-111 chloride (111InCl) solution is produced by proton irradiation of a cadmium target in a cyclotron, as recommended by International Atomic Energy Agency (IAEA). The former method is more commonly used as it results in a high level of radionuclide purity.

<span class="mw-page-title-main">DOTA-TATE</span> Eight amino-acid long peptide covalently bonded to a DOTA chelator

DOTA-TATE is an eight amino acid long peptide, with a covalently bonded DOTA bifunctional chelator.

<span class="mw-page-title-main">Edotreotide</span> Chemical compound

Edotreotide (USAN, also known as (DOTA0-Phe1-Tyr3) octreotide, DOTA-TOC, DOTATOC) is a substance which, when bound to various radionuclides, is used in the treatment and diagnosis of certain types of cancer. When used therapeutically it is an example of peptide receptor radionuclide therapy.

Advanced Accelerator Applications is a France-based pharmaceutical group, specialized in the field of nuclear medicine. The group operates in all three segments of nuclear medicine to diagnose and treat serious conditions in the fields of oncology, neurology, cardiology, infectious and inflammatory diseases.

<span class="mw-page-title-main">Pancreatic neuroendocrine tumor</span> Medical condition

Pancreatic neuroendocrine tumours, often referred to as "islet cell tumours", or "pancreatic endocrine tumours" are neuroendocrine neoplasms that arise from cells of the endocrine (hormonal) and nervous system within the pancreas.

<span class="mw-page-title-main">Peptide receptor radionuclide therapy</span> Type of radiotherapy

Peptide receptor radionuclide therapy (PRRT) is a type of radionuclide therapy, using a radiopharmaceutical that targets peptide receptors to deliver localised treatment, typically for neuroendocrine tumours (NETs).

Lutetium (<sup>177</sup>Lu) chloride Radioactive compound used for radiopharmaceutical labeling

Lutetium (177Lu) chloride is a radioactive compound used for the radiolabeling of pharmaceutical molecules, aimed either as an anti-cancer therapy or for scintigraphy. It is an isotopomer of lutetium(III) chloride containing the radioactive isotope 177Lu, which undergoes beta decay with a half-life of 6.65 days.

Arginine/lysine, sold under the brand name LysaKare, is a fixed-dose combination medication used to protect the kidneys from radiation damage during cancer treatment with a radioactive medicine called lutetium (177Lu) oxodotreotide. It contains L-arginine hydrochloride and L-lysine hydrochloride.

Copper (<sup>64</sup>Cu) oxodotreotide Radioactive diagnostic agent used in PET scan to localize tumors

Copper (64Cu) oxodotreotide or Copper Cu 64 dotatate, sold under the brand name Detectnet, is a radioactive diagnostic agent indicated for use with positron emission tomography (PET) for localization of somatostatin receptor positive neuroendocrine tumors (NETs) in adults.

Lutetium (<sup>177</sup>Lu) vipivotide tetraxetan Radiopharmaceutical medication

Lutetium (177Lu) vipivotide tetraxetan, sold under the brand name Pluvicto, is a radiopharmaceutical medication used for the treatment of prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC). Lutetium (177Lu) vipivotide tetraxetan is a targeted radioligand therapy.

<span class="mw-page-title-main">Somatostatin receptor antagonist</span> Class of chemical compounds

Somatostatin receptor antagonists are a class of chemical compounds that work by imitating the structure of the neuropeptide somatostatin. The somatostatin receptors are G protein-coupled receptors. Somatostatin receptor subtypes in humans are sstr1, 2A, 2 B, 3, 4 and 5. While normally expressed in the gastrointestinal (GI) tract, pancreas, hypothalamus, and central nervous system (CNS), they are expressed in different types of tumours. The predominant subtype in cancer cells is the ssrt2 subtype, which is expressed in neuroblastomas, meningiomas, medulloblastomas, breast carcinomas, lymphomas, renal cell carcinomas, paragangliomas, small cell lung carcinomas and hepatocellular carcinomas.

<span class="mw-page-title-main">Somatostatin inhibitor</span> Class of pharmaceuticals

Somatostatin receptor antagonists are a class of chemical compounds that work by imitating the structure of the neuropeptide somatostatin, which is an endogenous hormone found in the human body. The somatostatin receptors are G protein-coupled receptors. Somatostatin receptor subtypes in humans include sstr1, 2A, 2 B, 3, 4, and 5. While normally expressed in the gastrointestinal (GI) tract, pancreas, hypothalamus, and central nervous system (CNS), they are expressed in different types of tumours. The predominant subtype in cancer cells is the ssrt2 subtype, which is expressed in neuroblastomas, meningiomas, medulloblastomas, breast carcinomas, lymphomas, renal cell carcinomas, paragangliomas, small cell lung carcinomas, and hepatocellular carcinomas.

References

  1. ↑ "Summary Basis of Decision (SBD) for Lutathera". Health Canada . 23 October 2014. Retrieved 29 May 2022.
  2. ↑ "Lutathera 370 MBq/mL solution for infusion - Summary of Product Characteristics (SmPC)". (emc). Retrieved 9 July 2021.
  3. 1 2 "Lutathera- lutetium lu 177 dotatate injection". DailyMed. 4 May 2020. Retrieved 8 November 2020.
  4. 1 2 "Lutathera EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 11 December 2019. Retrieved 11 December 2019.
  5. ↑ Wang L, Tang K, Zhang Q, Li H, Wen Z, Zhang H, Zhang H (2013). "Somatostatin receptor-based molecular imaging and therapy for neuroendocrine tumors". BioMed Research International. 2013: 102819. doi: 10.1155/2013/102819 . PMC   3784148 . PMID   24106690.
  6. ↑ Ramage JK, Ahmed A, Ardill J, Bax N, Breen DJ, Caplin ME, et al. (January 2012). "Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs)". Gut. 61 (1): 6–32. doi:10.1136/gutjnl-2011-300831. PMC   3280861 . PMID   22052063.
  7. 1 2 Bodei L, Mueller-Brand J, Baum RP, Pavel ME, Hörsch D, O'Dorisio MS, et al. (May 2013). "The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours". European Journal of Nuclear Medicine and Molecular Imaging. 40 (5): 800–16. doi:10.1007/s00259-012-2330-6. PMC   3622744 . PMID   23389427.
  8. ↑ New Drug Therapy Approvals 2018 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2019. Retrieved 16 September 2020.
  9. ↑ "European approval of lutetium oxodotreotide for gastroenteropancreatic neuroendocrine (GEP-NET) tumours". ecancer.org. 2017-10-03. Archived from the original on 2018-04-03. Retrieved 2018-04-02.
  10. 1 2 3 4 5 6 7 "FDA approves new treatment for certain digestive tract cancers". U.S. Food and Drug Administration (FDA) (Press release). 26 January 2018. Archived from the original on 11 December 2019. Retrieved 11 December 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  11. ↑ "FDA approves lutetium Lu 177 dotatate for treatment of GEP-NETS". U.S. Food and Drug Administration (FDA) (Press release). 26 January 2018. Archived from the original on 11 December 2019. Retrieved 11 December 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  12. 1 2 3 4 5 6 7 8 9 10 "Drug Trials Snapshots: Lutathera". U.S. Food and Drug Administration (FDA). 20 February 2018. Archived from the original on 11 December 2019. Retrieved 11 December 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  13. ↑ MarketScreener (2024-04-23). "Novartis Gets FDA Approval for Lutathera in Pediatric Treatment - MarketScreener". uk.marketscreener.com. Retrieved 2024-04-23.
  14. ↑ Thompson L (7 February 2019). "Significance of Amino Acid Solution With Lutetium Lu 177 Dotatate". Oncology Nurse Advisor.
  15. ↑ "LysaKare EPAR". European Medicines Agency (EMA). 24 May 2019. Retrieved 22 July 2020.
  16. ↑ Volterrani D, Erba PA, Carrió I, Strauss HW, Mariani G (10 August 2019). Nuclear Medicine Textbook: Methodology and Clinical Applications. Springer. p. 782. ISBN   978-3-319-95564-3.
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