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General Description:

Trastuzumab deruxtecan, identified by CAS number 1826843-81-5, is a notable compound with significant therapeutic applications. 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. 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. Trastuzumab deruxtecan has been granted FDA approval for specific patients with HER-2 positive breast cancer who have failed other treatments. Promising results from a clinical trial prompted accelerated FDA approval for this indication on December 20, 2019. Trastuzumab deruxtecan was developed by Daiichi Sankyo in collaboration with AstraZeneca. In May 2022, trastuzumab deruxtecan was fully approved by the FDA.

Indications:

This drug is primarily indicated for: Trastuzumab deruxtecan is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy. It is also indicated to treat adults with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. Trastuzumab deruxtecan is also indicated to treat adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Trastuzumab deruxtecan undergoes metabolic processing primarily in: Trastuzumab deruxtecan is likely broken down into small peptides and amino acids through catabolism, just as the metabolism of endogenous IgG. 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. In vitro, DXd, the topoisomerase inhibitor portion of the drug, is found to be metabolized by CYP3A4. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Trastuzumab deruxtecan are crucial for its therapeutic efficacy: 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%). The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Trastuzumab deruxtecan is an important consideration for its dosing schedule: In a pharmacokinetic study, the median elimination half-life of trastuzumab deruxtecan was about 5.8 days. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Trastuzumab deruxtecan exhibits a strong affinity for binding with plasma proteins: The Dxd portion of the drug has a plasma protein binding estimated at 97%. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Trastuzumab deruxtecan from the body primarily occurs through: A pharmacokinetic study revealed that this drug was mainly excreted in the feces. Another study determined that 67% of a dose was excreted in the feces. Unmetabolized DXd was found in the urine during a pharmacokinetic study. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Trastuzumab deruxtecan is distributed throughout the body with a volume of distribution of: The estimated volume of distribution of trastuzumab deruxtecan in the central compartment is 2.77 L, according to a population based pharmacokinetic study. Pharmacokinetic studies found that the unchanged drug is distributed in the blood and is not significantly retained in tissues. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Trastuzumab deruxtecan is a critical factor in determining its safe and effective dosage: Trastuzumab deruxtecan is rapidly cleared from systemic circulation. 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. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Trastuzumab deruxtecan exerts its therapeutic effects through: Trastuzumab demonstrates antitumor activity against certain types of HER2 positive breast cancer, however, clinical trials are still ongoing to confirm its efficacy. By exploiting both targeted antibody and cytotoxic effects, trastuzumab deruxtecan can effectively destroy tumors. The FDA label warns of a potential risk for neutropenia, interstitial lung disease/pneumonitis, and left ventricular dysfunction following the use of this drug. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Trastuzumab deruxtecan functions by: 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. 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. 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. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Trastuzumab deruxtecan belongs to the None, classified under the direct parent group Peptides. This compound is a part of the Organic Compounds, falling under the Organic Acids superclass, and categorized within the Carboxylic Acids and Derivatives class, specifically within the Amino Acids, Peptides, and Analogues subclass.

Categories:

Trastuzumab deruxtecan is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antibodies, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antibody-drug Conjugates, Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, BCRP/ABCG2 Substrates, Blood Proteins, Cancer immunotherapy, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Substrates, Globulins, HER2 (Human Epidermal Growth Factor Receptor 2) inhibitors, HER2 Receptor Antagonists, Immunoglobulins, Immunologic Factors, Immunoproteins, Immunotherapy, MATE 2 Substrates, MATE substrates, MONOCLONAL ANTIBODIES AND ANTIBODY DRUG CONJUGATES, Noxae, OATP1B3 substrates, P-glycoprotein substrates, Proteins, Serum Globulins, Topoisomerase Inhibitors, Toxic Actions. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.