Lutetium (177Lu) oxodotreotide

Short description: Chelate of Lu-177 with DOTA-TATE, a peptide derivative bound to a DOTA molecule

Lutetium (177Lu) dotatate
INN: lutetium (177Lu) oxodotreotide

Clinical data
Trade names| Lutathera
AHFS/Drugs.com| Monograph
License data|

* EU EMA: by INN
* US DailyMed: Lutathera
* US FDA: Lutathera

Routes of
administration| Intravenous
Drug class| Antineoplastic agent
ATC code|

* V10XX04 (WHO)

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

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]-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|

* 437608-50-9
* acetate: 177943-89-4 Y

PubChem CID|

* 71587735

DrugBank|

* DB13985

UNII|

* AE221IM3BB
* acetate: 99R86Y6V0M Y

KEGG|

* D11033

Chemical and physical data
Formula| C65H87LuN14O19S2
Molar mass| 1607.58 g·mol−1
3D model (JSmol)|

* Interactive image

SMILES

* 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

* 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]

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]

## Contents

* 1 Clinical trials and drug approval
* 2 Adverse effects
* 3 References
* 4 External links

## 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]

## 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.[13] 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][14][15]

## References

1. ↑ "Summary Basis of Decision (SBD) for Lutathera". 23 October 2014. https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00433&lang=en.
2. ↑ "Lutathera 370 MBq/mL solution for infusion - Summary of Product Characteristics (SmPC)". https://www.medicines.org.uk/emc/product/12723/smpc.
3. ↑ 3.0 3.1 "Lutathera- lutetium lu 177 dotatate injection". 4 May 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=72d1a024-00b7-418a-b36e-b2cb48f2ab55.
4. ↑ 4.0 4.1 "Lutathera EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/lutathera.
5. ↑ "Somatostatin receptor-based molecular imaging and therapy for neuroendocrine tumors". BioMed Research International 2013: 102819. 2013. doi:10.1155/2013/102819. PMID 24106690.
6. ↑ "Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs)". Gut 61 (1): 6–32. January 2012. doi:10.1136/gutjnl-2011-300831. PMID 22052063.
7. ↑ 7.0 7.1 "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. May 2013. doi:10.1007/s00259-012-2330-6. PMID 23389427.
8. ↑ (PDF) ﻿New Drug Therapy Approvals 2018﻿ (Report). January 2019. https://www.fda.gov/media/120357/download. Retrieved 16 September 2020.
9. ↑ "European approval of lutetium oxodotreotide for gastroenteropancreatic neuroendocrine (GEP-NET) tumours". 2017-10-03. https://ecancer.org/news/12480-european-approval-of-lutetium-oxodotreotide-for-gastroenteropancreatic-neuroendocrine--gep-net--tumours.php.
10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 "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. 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. This article incorporates text from this source, which is in the public domain.
12. ↑ 12.00 12.01 12.02 12.03 12.04 12.05 12.06 12.07 12.08 12.09 "Drug Trials Snapshots: Lutathera". 20 February 2018. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-lutathera. This article incorporates text from this source, which is in the public domain.
13. ↑ "Significance of Amino Acid Solution With Lutetium Lu 177 Dotatate". 7 February 2019. https://www.oncologynurseadvisor.com/home/departments/advisor-forum/significance-of-amino-acid-solution-with-lutetium-lu-177-dotatate/.
14. ↑ "LysaKare EPAR". 24 May 2019. https://www.ema.europa.eu/en/medicines/human/EPAR/lysakare.
15. ↑ (in en) Nuclear Medicine Textbook: Methodology and Clinical Applications. Springer. 10 August 2019. p. 782. ISBN 978-3-319-95564-3. https://books.google.com/books?id=bY2oDwAAQBAJ&pg=PA782.

## External links

* "Lutetium Lu 177 dotatate". Drug Information Portal. U.S. National Library of Medicine. https://druginfo.nlm.nih.gov/drugportal/name/lutetium lu 177 dotatate.

* v
* t
* e

Therapeutic radiopharmaceuticals (ATC: V10)

Pain palliation|

* 153Sm
* Lexidronam
* 89Sr (Strontium chloride)

Adrenergic tumors|

* 131I
* Iobenguane

CD20 antibodies|

* 90Y
* Ibritumomab tiuxetan
* 131I
* Tositumomab

Radionuclides|

| alpha emitters|

* 223Ra (Radium chloride)

|

beta emitters|

* 32P
* 89Sr
* 90Y
* 131I
* 153Sm
* 165Dy
* 169Er
* 177Lu (Oxodotreotide)
* 186Re
* 198Au

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