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General Description:

Sacituzumab govitecan, identified by CAS number 1491917-83-9, is a notable compound with significant therapeutic applications. Metastatic triple-negative breast cancer (mTNBC) is an aggressive form of breast cancer with limited treatment options involving cytotoxic chemotherapy agents. Targeted chemotherapy through the application of antibody-conjugated agents (ADCs) is a recent advance in cancer treatment. One such ADC is sacituzumab govitecan, which combines a humanized anti-trophoblast cell-surface antigen 2 (TROP-2) antibody with the topoisomerase I inhibitor SN-38. Sacituzumab govitecan was granted FDA approval on April 22nd, 2020 and is marketed under the brand name Trodelvy™ by Immunomedics, Inc.; it is currently indicated under accelerated approval for the treatment of mTNBC patients who have undergone two or more prior therapies. As a targeted cytotoxic agent, it is hoped to provide similar efficacy with reduced adverse effects. In November 2021, sacituzumab govitecan was also approved by the European Commission.

Indications:

This drug is primarily indicated for: Sacituzumab govitecan is indicated for adult patients with metastatic triple-negative breast cancer (mTNBC) who have undergone two or more prior therapies for metastatic disease. Sacituzumab govitecan is also indicated for the treatment of locally advanced or metastatic urothelial cancer in adult patients who have received previous platinum-based therapy and either a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor. This indication has been approved under accelerated approval, and continued approval may be contingent on the demonstration of clinical benefit in confirmatory trials. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Sacituzumab govitecan undergoes metabolic processing primarily in: The metabolism of sacituzumab govitecan has not been extensively studied. The SN-38 moiety is known to undergo O-glucuronidation by UGT1A1, presumably in the liver, and the SN-38 glucuronide metabolite SN-38G is found in the serum of patients undergoing treatment. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Sacituzumab govitecan are crucial for its therapeutic efficacy: In patients receiving 10 mg/kg sacituzumab govitecan the C_max of the conjugate was 243,000 ± 45,600 ng/mL while the C_max of free SN-38 was 127 ± 60 ng/mL. Similarly, the AUC_0-168 for the conjugate/free SN-38 was 5,210,000 ± 1,230,000 and 3,900 ± 1,830 ng\*h/mL, respectively. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Sacituzumab govitecan is an important consideration for its dosing schedule: Sacituzumab govitecan has a mean half-life of 16 hours, while free SN-38 has a mean half-life of 18 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Sacituzumab govitecan exhibits a strong affinity for binding with plasma proteins: SN-38, the active moiety, remains mostly bound to the IgG component in serum. In patients administered with 10 mg/kg of sacituzumab govitecan, free SN-38 serum levels were measured as 2.3% and 4.5% at 30 minutes and one day, respectively. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Sacituzumab govitecan from the body primarily occurs through: No detailed information exists for sacituzumab govitecan elimination; renal elimination of SN-38 is known to be minimal, and it is expected that the fecal route will be the major contributor. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Sacituzumab govitecan is distributed throughout the body with a volume of distribution of: Sacituzumab govitecan has a mean volume of distribution of 0.045 L/kg. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Sacituzumab govitecan is a critical factor in determining its safe and effective dosage: Sacituzumab govitecan has a clearance rate of 0.002 L/h/kg. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Sacituzumab govitecan exerts its therapeutic effects through: Sacituzumab govitecan is a humanized monoclonal antibody/topoisomerase inhibitor conjugate designed to induce DNA damage-mediated cell death preferentially in TROP-2-expressing cancer cells. Detailed pharmacodynamic studies have not been performed for sacituzumab govitecan, although as a therapeutic protein, there is potential for immunogenicity. In addition, sacituzumab govitecan has the potential to cause severe hypersensitivity, nausea and vomiting, and embryo-fetal toxicity. Patients who are homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Sacituzumab govitecan functions by: Sacituzumab govitecan is an antibody-drug conjugate (ADC) targeting TROP-2-expressing cancer cells to induce DNA-damage-mediated cell death. The conjugate comprises a humanized anti-TROP-2 monoclonal antibody (RS7-3G11, also known as RS7) chemically linked by a hydrolyzable CL2A linker to the cytotoxic drug SN-38. The proposed mechanism of action first involves the binding of the RS7 component to TROP-2, which is highly expressed on the cell surface of multiple cancers. Binding of RS7 to TROP-2 results in rapid internalization of bound antibody, and the likely intracellular release of SN-38 via hydrolysis of the CL2A linker. SN-38 is an active metabolite of the anti-cancer drug , which is thought to work primarily through inhibition of DNA topoisomerase I, leading to DNA damage and eventual cell death. In addition, recent work has identified a possible secondary mechanism of action for SN-38 by disrupting the binding of Far Upstream Binding Protein 1 (FUBP1) to the _FUSE_ elements regulating oncogene expression. In addition to SN-38-mediated cell death, there is also some evidence that the RS7 component of the conjugate drug possesses antibody-directed cellular toxicity. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Sacituzumab govitecan 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:

Sacituzumab govitecan is categorized under the following therapeutic classes: Alkaloids, Amino Acids, Peptides, and Proteins, Antibodies, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antibody-drug Conjugates, Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, Blood Proteins, Cancer immunotherapy, Globulins, Immunoglobulins, Immunologic Factors, Immunoproteins, Immunotherapy, MONOCLONAL ANTIBODIES AND ANTIBODY DRUG CONJUGATES, Noxae, Proteins, Serum Globulins, Topoisomerase Inhibitors, Toxic Actions, Trop-2-Directed Monoclonal Antibodies, UGT1A1 Substrates. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.