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General Description:

Luspatercept, identified by CAS number 1373715-00-4, is a notable compound with significant therapeutic applications. Luspatercept is a recombinant fusion protein comprised of a modified extracellular domain of activin receptor type IIB fused to the FC domain of human IgG1. It was first approved for use in the United States in November 2019 under the brand name Reblozyl® for the treatment of anemia in patients with beta thalassemia who require regular blood transfusions. Luspatercept is novel in that it ameliorates anemia via action on late-stage erythropoiesis, in contrast to typical erythropoiesis-stimulating agents (ESAs), such as and , which act only on early-stage erythropoiesis. Luspatercept's novel mechanism of action, then, is uniquely suited for the treatment of conditions in which late-stage erythropoiesis is defective, such as beta thalassemia and other myelodysplastic diseases.

Indications:

This drug is primarily indicated for: Luspatercept is indicated for the treatment of anemia in adults with beta thalassemia who require regular red blood cell transfusions. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Luspatercept undergoes metabolic processing primarily in: As luspatercept is a fusion protein, it is expected to undergo catabolism into amino acids by general protein degradation processes. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Luspatercept are crucial for its therapeutic efficacy: At doses of 1 mg/kg and 1.25 mg/kg, the average steady-state AUC was 126 day•μg/mL and 157 day•μg/mL and the average C_max was 8.17 μg/mL and 10.2 μg/mL, respectively. Steady-state was reached after 3 doses given every 3 weeks. T_max is reached approximately 7 days after administration. Absorption pharmacokinetics do not appear to be affected by the site of subcutaneous injection. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Luspatercept is an important consideration for its dosing schedule: The average half-life of luspatercept is approximately 11 days. This determines the duration of action and helps in formulating effective dosing regimens.

Volume of Distribution:

Luspatercept is distributed throughout the body with a volume of distribution of: The average apparent volume of distribution is 7.1 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Luspatercept is a critical factor in determining its safe and effective dosage: The total apparent clearance of luspatercept is 0.44 L/day. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Luspatercept exerts its therapeutic effects through: Luspatercept binds to, and inhibits, several ligands that act as negative regulators of late-stage erythropoiesis, thereby alleviating the ineffective erythropoiesis observed in patients with beta thalassemia. Thromboembolic events (e.g. deep vein thrombosis, pulmonary embolism, ischemic stroke) have been reported in patients with beta thalassemia receiving luspatercept - patients with a greater baseline risk of thromboembolism may benefit from concomitant thromboprophylaxis while undergoing therapy with luspatercept. Luspatercept may carry some degree of embryo-fetal toxicity and should therefore be avoided in pregnancy. Women of child-bearing age should use an effective form of contraception during therapy and for 3 months after completion of therapy. Luspatercept may also lead to the development of extramedullary hematopoietic (EMH) masses in adult patients with transfusion-dependent beta-thalassemia. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Luspatercept functions by: Beta thalassemia is a genetic red blood cell disorder caused by mutations in the β-globin gene - these mutations cause oxidative stress and premature apoptosis of erythroblasts, thereby leading to ineffective erythropoesis. The transforming growth factor beta (TGF-β) superfamily of endogenous ligands (including activins, growth differentiation factors, and bone morphogenetic proteins) are involved in the inhibition of erythroid differentiation via activation of the Smad2/3 subfamily of intracellular effectors. Luspatercept is a fusion protein comprising a modified extracellular domain of activin receptor type IIB (a target for many TGF-β ligands) fused to the FC domain of human IgG1. Luspatercept ameliorates ineffective erythropoiesis in patients with beta thalassemia by acting as a "ligand trap" for various members of the TGF-β superfamily, preventing their downstream signalling and subsequent inhibition of late-stage erythroid maturation. The specific members of the TGF-β superfamily targeted by luspatercept are currently unknown, though growth differentiation factor 11 (GDF11) has been experimentally excluded as a potential target. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Luspatercept 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:

Luspatercept is categorized under the following therapeutic classes: Activin Receptors, Amino Acids, Peptides, and Proteins, Antianemia Drugs, Antianemic Preparations, Blood and Blood Forming Organs, Enzymes, Enzymes and Coenzymes, Erythroid Maturation Agents, Globulins, Hematinics, Hematologic Agents, Immunoglobulin Constant Regions, Immunoglobulin Fragments, Immunoproteins, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Peptide Fragments, Peptides, Phosphotransferases, Phosphotransferases (Alcohol Group Acceptor), Protein Kinases, Protein-Serine-Threonine Kinases, Proteins, Receptors, Growth Factor, Receptors, Peptide, Receptors, Transforming Growth Factor beta, Recombinant Proteins, Transferases. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Luspatercept include:

• Molecular Weight: 76000.0