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| Primary information |
|---|
| ID | 15687 |
| Therapeutic ID | Th1619 |
| Protein Name | Trastuzumab deruxtecan |
| Sequence | NA
|
| Molecular Weight | NA |
| Chemical Formula | NA |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | In a pharmacokinetic study, the median elimination half-life of trastuzumab deruxtecan was about 5.8 days.[L10842] |
| Description | Trastuzumab deruxtecan is a HER-2 directed antibody attached to a topoisomerase inhibitor that is approved for use in certain types of metastatic, unresectable breast cancer.[L10842] It is classified as an antibody-drug conjugate. The cleavable peptide linker used to bind the antibody and drug in this product distinguishes it from other members of its class.[A188988] Trastuzumab deruxtecan has been granted FDA approval for specific patients with HER-2 positive breast cancer who have failed other treatments.[L10842] Promising results from a clinical trial prompted accelerated FDA approval for this indication on December 20, 2019.[L10845] Trastuzumab deruxtecan was developed by Daiichi Sankyo in collaboration with AstraZeneca. The continued approval of this drug will depend on the confirmation of its beneficial effects in ongoing clinical trials.[L10842] |
| Indication/Disease | Trastuzumab deruxtecan is indicated for the treatment of adult patients with HER-2 positive breast cancer that is unresectable or metastatic and was previously treated with at least 2 anti-HER2-based regimens while the cancer was metastatic.[L10842] Continued approval will depend on the results of clinical trial results confirming its clinical benefit.[L10842] |
| Pharmacodynamics | Trastuzumab demonstrates antitumor activity against certain types of HER2 positive breast cancer, however, clinical trials are still ongoing to confirm its efficacy.[A188982,L10842,L10845] By exploiting both targeted antibody and cytotoxic effects, trastuzumab deruxtecan can effectively destroy tumors.[A188988] The FDA label warns of a potential risk for neutropenia, interstitial lung disease/pneumonitis, and left ventricular dysfunction following the use of this drug.[L10842] |
| Mechanism of Action | Trastuzumab deruxtecan is a humanized anti-HER2 IgG1 antibody, targeting cancer cause by mutation of the HER2 gene. In addition, the small molecule portion of this drug, deruxtecan (DXd), is a topoisomerase I inhibitor.[A188976,L10842] It is attached to the antibody by a peptide linker. After trastuzumab deruxtecan binds to HER2 found on malignant cells, it is internalized and linker cleavage occurs through the actions of lysosomal enzymes. After it is released through cleavage, DXd causes targeted DNA damage and apoptosis in cancer cells, due to the ability to cross cell membranes.[A188988,L10842] Normally, drugs in this class (antibody-drug conjugates) present a challenge. The monoclonal antibody accurately targets cancer cells, however exert limited killing action. The addition of a cytotoxic agent (a topoisomerase I inhibitor in this case) effectively kills dividing cancer cells, including those in the healthy tissues, leading to various adverse effects. The peptide linker used to formulate this drug is cleavable, which is unique to other antibody-drug conjugates, allowing for increased efficacy and reduced drug resistance to topoisomerase.[A188988] |
| Toxicity | LD50 and overdose information are not currently available, but effects of an overdose are likely to impact the lungs, heart, and circulatory system, leading to significant toxicity.[L10842] |
| Metabolism | Trastuzumab deruxtecan is likely broken down into small peptides and amino acids through catabolism, just as the metabolism of endogenous IgG.[A189009,L10842] Cathepsin B and L enzymes are thought to be involved in the cleavage of the peptide linker that joins the topoisomerase I inhibitor and the antibody.[A188988] In vitro, DXd, the topoisomerase inhibitor portion of the drug, is found to be metabolized by CYP3A4.[L10842] |
| Absorption | The Cmax of trastuzumab deruxtecan at normal therapeutic doses was 122 µg/mL (20%). The AUC of trastuzumab deruxtecan was 735 µg·day/mL (31%).[L10842] |
| The estimated volume of distribution of trastuzumab deruxtecan in the central compartment is 2.77 L, according to a population based pharmacokinetic study.[L10842] Pharmacokinetic studies found that the unchanged drug is distributed in the blood and is not significantly retained in tissues.[A188979] |
| Clearance | Trastuzumab deruxtecan is rapidly cleared from systemic circulation.[A188979] Estimated systemic clearance of trastuzumab deruxtecan is 0.42 L/day, according to a population pharmacokinetic analysis. DXd showed a systemic clearance of about 19.2 L/h.[L10842] |
| Categories | Amino Acids, Peptides, and Proteins |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | High affinity immunoglobulin gamma Fc receptor I,DNA topoisomerase 1 |
| Brand Name | Enhertu |
| Company | Daiichi Sankyo, Inc. |
| Brand Description | Daiichi Sankyo, Inc. |
| Prescribed For | Intravenous |
| Chemical Name | 100 mg/5mL |
| Formulation | None. |
| Physical Appearance | nausea, vomiting, fatigue, hair loss, constipation, decreased appetite, anemia, low white blood cell count (neutropenia, leukopenia), diarrhea, cough, and low platelets (thrombocytopenia), abdominal pain, inflammation of the mouth and lips, indigestion/heartburn, rash, low potassium (hypokalemia), shortness of breath, nosebleed, interstitial lung disease, headache, dizziness, upper respiratory tract infection, increased aspartate aminotransferase, alanine aminotransferase, and dry eye |
| Route of Administration | Enhertu is a medicine used in adults to treat HER2-positive cancers which includes specific types of breast cancers and stomach cancers. Enhertu is made up of two cancer-fighting medicines, a targeted cancer therapy and a chemotherapy drug. Enhertu is usually given as an infusion into a vein every... |
| Recommended Dosage | ENHERTU is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. |
| Contraindication | NA |
| Side Effects | Fam-trastuzumab deruxtecan-nxki is a HER2-directed antibody and topoisomerase inhibitor conjugate. Fam-trastuzumab deruxtecan-nxki is an antibody-drug conjugate (ADC) composed of three components: 1) a humanized anti-HER2 IgG1 monoclonal antibody (mAb), covalently linked to 2) a topoisomerase inhibitor, via 3) a tetrapeptide-based cleavable linker. Deruxtecan is composed of a protease-cleavable maleimide tetrapeptide linker and the topoisomerase inhibitor, DXd, which is an exatecan derivative. |
| Useful Link 1 | Link |
| Useful Link 2 | Link |
| Remarks | NA |