Technetium Tc-99m tilmanocept

Identification

Name
Technetium Tc-99m tilmanocept
Accession Number
DB09266
Type
Small Molecule
Groups
Approved, Investigational
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].

Synonyms
  • Technetium (99mTc) tilmanocept
  • Technetium Tc 99m Tilmanocept
  • Technetium Tc99 tilmanocept
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Kit for the preparation of Lymphoseek (technetium Tc 99m tilmanocept)Kit250 ug/1Cardinal Health 414, Llc2017-09-20Not applicableUs
Kit for the preparation of Lymphoseek (technetium Tc 99m tilmanocept)Kit250 ug/1Cardinal Health 414, Llc2017-09-20Not applicableUs
Kit for the preparation of Lymphoseek (technetium Tc 99m tilmanocept)Kit250 ug/1Navidea Biopharmaceuticals, Inc.2016-10-202019-06-01Us
Kit for the preparation of Lymphoseek (technetium Tc 99m tilmanocept)Kit250 ug/1Navidea Biopharmaceuticals, Inc.2013-03-132019-06-01Us
Categories
UNII
8IHI69PQTC
CAS number
1262984-82-6
Weight
Not Available
Chemical Formula
Not Available
InChI Key
Not Available
InChI
Not Available
IUPAC Name
Not Available
SMILES
Not Available

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
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.

TargetActionsOrganism
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].

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
DrugInteraction
ArticaineArticaine may decrease effectiveness of Technetium Tc-99m tilmanocept as a diagnostic agent.
BenzocaineBenzocaine may decrease effectiveness of Technetium Tc-99m tilmanocept as a diagnostic agent.
Benzyl alcoholBenzyl alcohol may decrease effectiveness of Technetium Tc-99m tilmanocept as a diagnostic agent.
BupivacaineBupivacaine may decrease effectiveness of Technetium Tc-99m tilmanocept as a diagnostic agent.
ButacaineButacaine may decrease effectiveness of Technetium Tc-99m tilmanocept as a diagnostic agent.
ButanilicaineButanilicaine may decrease effectiveness of Technetium Tc-99m tilmanocept as a diagnostic agent.
CapsaicinCapsaicin may decrease effectiveness of Technetium Tc-99m tilmanocept as a diagnostic agent.
ChloroprocaineChloroprocaine may decrease effectiveness of Technetium Tc-99m tilmanocept as a diagnostic agent.
CinchocaineCinchocaine may decrease effectiveness of Technetium Tc-99m tilmanocept as a diagnostic agent.
CocaineCocaine may decrease effectiveness of Technetium Tc-99m tilmanocept as a diagnostic agent.
Food Interactions
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
ATC Codes
V09IA09 — Technetium (99mtc) tilmanocept
FDA label
Download (281 KB)
MSDS
Download (124 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingDiagnosticCarcinoma, Colorectal / Hepatic Metastases1
1Active Not RecruitingDiagnosticNASH - Nonalcoholic Steatohepatitis / Nonalcoholic Steatohepatitis1
1CompletedDiagnosticRheumatoid Arthritis1
1RecruitingDiagnosticHuman Immunodeficiency Virus (HIV) / Human Immunodeficiency Virus (HIV) Infections / Kaposi s Sarcoma (KS)1
2CompletedDiagnosticKaposi s Sarcoma (KS)1
2CompletedDiagnosticMalignant Neoplasm of Colon / Rectal Carcinoma1
2RecruitingDiagnosticMelanoma / Rhabdomyosarcomas1
2TerminatedDiagnosticUterine Cervical Neoplasms1
2WithdrawnDiagnosticAnal Carcinoma1
3CompletedDiagnosticCancer, Breast / Melanoma1
3CompletedTreatmentCancer, Breast / Melanoma1
3TerminatedDiagnosticHead and Neck Squamous Cell Carcinoma (HNSCC)1
4CompletedNot AvailableCancer, Breast1
4CompletedDiagnosticCancer, Breast1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Kit250 ug/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6409990No2002-06-252020-05-12Us
US9439985No2016-09-132033-09-27Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)100MSDS
Predicted Properties
Not Available
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Ligand
General Function
Mediates the endocytosis of glycoproteins by macrophages. Binds both sulfated and non-sulfated polysaccharide chains.
Specific Function
Mannose binding
Gene Name
MRC1
Uniprot ID
P22897
Uniprot Name
Macrophage mannose receptor 1
Molecular Weight
166010.315 Da

Drug created on October 27, 2015 17:51 / Updated on November 02, 2018 07:00