Technetium Tc-99m tilmanocept

Identification

Name

Technetium Tc-99m tilmanocept

Accession Number

DB09266

Description

Technetium Tc-99m tilmanocept is a radiopharmaceutical diagnostic imaging agent approved by the U.S. Food and Drug Administration (FDA) for the imaging of lymph nodes with or without scintigraphic imaging. It is a macromolecule consisting of multiple units of diethylenetriaminepentaacetic acid (DTPA) and mannose, each covalently attached to a 10 kDa dextran backbone ^Label. DTPA serves as a chelating agent for technetium Tc 99m to bind ^Label. Technetium Tc-99m tilmanocept is used in lymphatic mapping and lymph node localization in breast cancer, melanoma, clinically node-negative squamous cell carcinoma of the oral cavity, and other solid tumors ^2,3. Detecting sentinel lymph node (SLN) is clinically useful in the prognosis and management of the disease, as it is considered as the first lymph node that receives afferent lymphatic drainage from a primary tumor, and may be used to predict tumour staging and metastasis ³. However, as nodal micrometastasis in breast cancer may not be associated with significant changes in survival, it is also important to identify clinically node-negative patients ³.

Technetium Tc-99m tilmanocept is a novel CD206 receptor-targeted molecule that selectively binds to mannose receptors expressed on the surface of reticuloendothelial cells in lymph nodes ¹. Due to its relatively small molecular weight and small molecular diameter of 7 nm ¹, technetium Tc-99m tilmanocept displays more rapid injection site clearance, high sentinel node extraction, and low distal node accumulation compared to other conventional radiocolloids ³. It achieves high overall accuracy in detecting SLN ². Once reconstituted and labelled, technetium Tc99m tilmanocept is intended to be injected in close proximity to the tumor being diagnosed and employed in preoperative gamma detection imaging in combination with various other techniques, including scintigraphy, SPECT, and SPECT/CT ⁴. It may be administered via subcutaneous, intradermal, subareolar, or peritumoral injection, depending on the tutor location and planned injection technique ^Label. It is marketed under the trade name Lymphoseek. Potential application of technetium Tc-99m tilmanocept to other cancers are being investigated ³.

Type

Small Molecule

Groups

Approved, Investigational

Synonyms

• Technetium (99mTc) tilmanocept
• Technetium Tc 99m Tilmanocept
• Technetium Tc99 tilmanocept

Pharmacology

Indication

Indicated with or without scintigraphic imaging for lymphatic mapping using a handheld gamma counter to locate lymph nodes draining a primary tumor site in patients with solid tumors for which this procedure is a component of intraoperative management ^Label.

Indicated with or without scintigraphic imaging for guiding sentinel lymph node biopsy using a handheld gamma counter in patients with clinically node negative squamous cell carcinoma of the oral cavity, breast cancer or melanoma ^Label.

Associated Conditions

• Squamous Cell Carcinoma (SCC)
• Squamous Cell Carcinoma of the Oral Cavity
• Tumors, Solid

Contraindications & Blackbox Warnings

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Pharmacodynamics

Technetium Tc 99m tilmanocept binds to the CD206 receptors on the surface of reticuloendothelial cells, such as macrophages and dendritic cells, which are highly expressed in lymph nodes. In clinical studies, technetium Tc 99m tilmanocept has been shown to be detectable in lymph nodes within 10 minutes and up to 30 hours after injection ^Label. Moreover, Phase 1 clinical studies showed approximately 0.5 to 1.8% of a dose accumulating in draining lymph nodes via specific binding after about 30 minutes. Technetium Tc99m tilmanocept bindng appears to be independent of tumor type or severity ⁴. It displays rapid injection site clearance, rapid accumulation, long retention in the sentinel node, and low distal node accumulation ³.

Mechanism of action

The mannose of the molecule acts as a ligand and guides the molecule to selectively bind to human mannose binding receptors (CD206) located on the surface of reticuloendothelial cells residing within lymph nodes, such as macrophages and dendritic cells ^Label. According to in vitro studies, technetium Tc 99m tilmanocept demonstrates selective binding to CD206 with a primary binding site affinity of Kd = 2.76 x 10^-11 M.

Target	Actions	Organism
AMacrophage mannose receptor 1	ligand	Humans

Absorption

In clinical studies, technetium Tc 99m tilmanocept was detectable in lymph nodes within 10 minutes and up to 30 hours after injection. The maximum amount of the accumulated radioactive dose in the liver, kidney, and bladder was reached at 1 hour post-injection and was approximately 1-2% of the total, injected dose in each tissue ^Label.

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Although the metabolism of technetium Tc 99m tilmanocept has not yet been experimentally investigated, tilmanocept may be metabolized in the liver to its main component molecules dextran, mannose and diethylenetriaminepentaacetic acid (DTPA). Subsequently, dextran may be further broken down into glucose. Furthermore, given the predominant role of the liver in the metabolism of technetium Tc 99m tilmanocept, some biliary elimination of the radiopharmaceutical is also expected. [L1557]

Route of elimination

It is believed that technetium Tc 99m tilmanocept is eliminated primarily through the kidneys as primary metabolites. Technetium Tc 99m tilmanocept may undergo hepatic elimination and biliary elimination [L1557]

Half-life

Technetium Tc99m tilmanocept decays by isomeric transition with a physical half-life of approximately 6 hours. The half-life at the injection site of 1.8 to 3.1 hours ^Label.

Clearance

In dose-ranging clinical studies, injection site clearance rates were similar across doses ranging from 4 to 200 mcg with a mean elimination rate constant in the range of 0.222 to 0.396/hr ^Label.

Adverse Effects

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Toxicity

Tilmanocept was not mutagenic in vitro in the Ames bacterial mutation assay and in the in vitro mouse lymphoma test, and was negative in the in vivo micronucleus test in mice. Studies assessing the carcinogenic potential or effects on reproductive fertility have not been conducted ^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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Articaine	Articaine may decrease effectiveness of Technetium Tc-99m tilmanocept as a diagnostic agent.
Benzocaine	Benzocaine may decrease effectiveness of Technetium Tc-99m tilmanocept as a diagnostic agent.
Benzyl alcohol	Benzyl alcohol may decrease effectiveness of Technetium Tc-99m tilmanocept as a diagnostic agent.
Bupivacaine	Bupivacaine may decrease effectiveness of Technetium Tc-99m tilmanocept as a diagnostic agent.
Capsaicin	Capsaicin may decrease effectiveness of Technetium Tc-99m tilmanocept as a diagnostic agent.
Chloroprocaine	Chloroprocaine may decrease effectiveness of Technetium Tc-99m tilmanocept as a diagnostic agent.
Cinchocaine	Cinchocaine may decrease effectiveness of Technetium Tc-99m tilmanocept as a diagnostic agent.
Cocaine	Cocaine may decrease effectiveness of Technetium Tc-99m tilmanocept as a diagnostic agent.
Diphenhydramine	Diphenhydramine may decrease effectiveness of Technetium Tc-99m tilmanocept as a diagnostic agent.
Dyclonine	Dyclonine may decrease effectiveness of Technetium Tc-99m tilmanocept as a diagnostic agent.

Additional Data Available

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Severity
Severity
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Evidence Level
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Food Interactions

No interactions found.

Products

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
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Kit for the preparation of Lymphoseek (technetium Tc 99m tilmanocept)	Kit	250 ug/1	Intradermal; Subcutaneous	Navidea Biopharmaceuticals, Inc.	2016-10-20	2019-06-01
Kit for the preparation of Lymphoseek (technetium Tc 99m tilmanocept)	Kit	250 ug/1	Intradermal; Subcutaneous	Cardinal Health 414, Llc	2017-09-20	Not applicable
Kit for the preparation of Lymphoseek (technetium Tc 99m tilmanocept)	Kit	250 ug/1	Intradermal; Subcutaneous	Navidea Biopharmaceuticals, Inc.	2013-03-13	2019-06-01
Kit for the preparation of Lymphoseek (technetium Tc 99m tilmanocept)	Kit	250 ug/1	Intradermal; Subcutaneous	Cardinal Health 414, Llc	2017-09-20	Not applicable

Additional Data Available

Application Number
Application Number
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Product Code
Product Code
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Categories

ATC Codes

V09IA09 — Technetium (99mtc) tilmanocept

• V09IA — Technetium (99mTc) compounds
• V09I — TUMOUR DETECTION
• V09 — DIAGNOSTIC RADIOPHARMACEUTICALS
• V — VARIOUS

Drug Categories

• Diagnostic Radiopharmaceuticals
• Radioactive Diagnostic Agent
• Radiopharmaceutical Activity
• Technetium (99Mtc) Compounds
• Tumour Detection

Classification

Not classified

Chemical Identifiers

UNII

8IHI69PQTC

CAS number

1262984-82-6

InChI Key

Not Available

InChI

Not Available

IUPAC Name

Not Available

SMILES

Not Available

References

General References

1. Wallace AM, Han LK, Povoski SP, Deck K, Schneebaum S, Hall NC, Hoh CK, Limmer KK, Krontiras H, Frazier TG, Cox C, Avisar E, Faries M, King DW, Christman L, Vera DR: Comparative evaluation of [(99m)tc]tilmanocept for sentinel lymph node mapping in breast cancer patients: results of two phase 3 trials. Ann Surg Oncol. 2013 Aug;20(8):2590-9. doi: 10.1245/s10434-013-2887-8. Epub 2013 Mar 17. [PubMed:23504141]
2. Agrawal A, Civantos FJ, Brumund KT, Chepeha DB, Hall NC, Carroll WR, Smith RB, Zitsch RP, Lee WT, Shnayder Y, Cognetti DM, Pitman KT, King DW, Christman LA, Lai SY: [(99m)Tc]Tilmanocept Accurately Detects Sentinel Lymph Nodes and Predicts Node Pathology Status in Patients with Oral Squamous Cell Carcinoma of the Head and Neck: Results of a Phase III Multi-institutional Trial. Ann Surg Oncol. 2015 Oct;22(11):3708-15. doi: 10.1245/s10434-015-4382-x. Epub 2015 Feb 11. [PubMed:25670018]
3. Surasi DS, O'Malley J, Bhambhvani P: 99mTc-Tilmanocept: A Novel Molecular Agent for Lymphatic Mapping and Sentinel Lymph Node Localization. J Nucl Med Technol. 2015 Jun;43(2):87-91. doi: 10.2967/jnmt.115.155960. Epub 2015 May 8. [PubMed:25956693]
4. Electronic Medicines Compendium: Lymphoseek (technetium TC 99M tilmanocept) Monograph [Link]

External Links

PubChem Substance

347910428

RxNav

1373391

FDA label

Download (281 KB)

MSDS

Download (124 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Diagnostic	Breast Cancer	1
3	Completed	Diagnostic	Breast Cancer / Melanoma	1
3	Completed	Treatment	Breast Cancer / Melanoma	1
2	Not Yet Recruiting	Diagnostic	Endometrial Cancer	1
1	Terminated	Diagnostic	Carcinoma, Colorectal / Hepatic Metastases	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Kit	Intradermal; Subcutaneous	250 ug/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
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US6409990	No	2002-06-25	2020-05-12
US9439985	No	2016-09-13	2033-09-27

Additional Data Available

Filed On
Filed On
Available for Purchase
The date on which a patent was filed with the relevant government.
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Properties

State

Solid

Experimental Properties

Property	Value	Source
boiling point (°C)	100	MSDS

Predicted Properties

Not Available

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

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Drug created on October 27, 2015 17:51 / Updated on June 12, 2020 11:42