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Sarilumab API Manufacturers & Suppliers

General Description:

Sarilumab, identified by CAS number 1189541-98-7, is a notable compound with significant therapeutic applications. Sarilumab is a fully human anti-IL-6R monoclonal IgG1 antibody that binds to both membrane bound and soluble interleukin 6 (IL-6) receptor forms, thus blocking the cis- and trans-inflammatory signalling cascades of IL-6 . Sarilumab was developped by Sanofi and Regeneron Pharmaceuticals, Inc; it was US FDA-approved in May 2017 and followed by EU approval in June 2017 for the treatment of moderate to severe Rheumatoid Arthritis (RA) in combination with methotrexate . RA is a chronic inflammatory disease characterized by polyarthritis and its treatment has been challenged by the different response in every patient . Subcutaneous administration of Sarilumab has been shown to decrease acute-phase reactant levels and improve in clinical RA symptoms .

Indications:

This drug is primarily indicated for: Indicated for modere to severe reactive RA in adult patients who are irresponsive, respond inadequately or present intolerance to disease-modifying anti-rheumatic drugs (DMARDs) or tumor necrosis factor (TNF) antagonists. It is indicated to be used in combination with methotrexate (MTX) or as a monotherapy when there is intolerance to MTX or MTX administration is inappropriate. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Sarilumab undergoes metabolic processing primarily in: The metabolism of Sarilumab has not been characterized. As it is a monoclonal antibody, It is thought to be degraded into small peptides and amino acids . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Sarilumab are crucial for its therapeutic efficacy: Sarilumab is shown to be well absorbed in RA patients after single SC administration with a maximum of serum concentration presented after 2 to 4 days. For the 150 mg every two weeks dose regimen, the AUC, Cmin and Cmax of sarilumab were 202 ± 120 mg.day/L, 6.35 ± 7.54 mg/L, and 20.0 ± 9.20 mg/L, respectively. For the 200 mg every two weeks dose regimen, the AUC, Cmin and Cmax of sarilumab were 395 ± 207 mg.day/L, 16.5 ± 14.1 mg/L, and 35.6 ± 15.2 mg/L, respectively . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Sarilumab is an important consideration for its dosing schedule: The half life will depend on the administered concentration. At 200 mg every 2 weeks, half-life is up to 10 days in patients with RA at steady state. At 150 mg every 2 weeks, half-life is up to 8 days in patients with RA at steady state. After the last steady state dose of 150 mg and 200 mg, the time to reach nondetectable concentration is 28 and 43 days, respectively . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Sarilumab exhibits a strong affinity for binding with plasma proteins: Sarilumab is a covalent heterotetramer composed by two disulfide linked heavy chains covelently linked to a kappa light chain. The heavy chain has a IgG1 constant region with a single N-linked glycosylation site in the Fc portion of the molecule. The complimentarity-determining regions (CDRs) within variable domains of both light and heavy chains combine to form the binding site for IL-6R. As Sarilumab is an IgG1 molecule, it presents Fc-effector function and it is prompt to bind to FcγRI, FcγRIIa, FCγRIIb, FcγRIIIa and FcγRIIIB. However, it does not induce Antibody-Dependant Cell-mediated Cytotoxicity (ADCC) or Complement-Dependant Cytotoxicity (CDC) . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Sarilumab from the body primarily occurs through: At high concentrations, Sarilumab is thought to be eliminated predominantly through a non-saturated proteolytic pathway, while at lower concentrations, the elimination will be done by saturable target-mediated elimination . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Sarilumab is distributed throughout the body with a volume of distribution of: In patients with RA, the apparent volume of distribution at steady state was 7.3 L . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Sarilumab is a critical factor in determining its safe and effective dosage: Sarilumab is not eliminated via renal or hepatic pathways. RA patients have shown a trend toward higher clearance in presence of anti-sarilumab antibodies . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Sarilumab exerts its therapeutic effects through: Single-dose subcutaneous administration of Sarilumab produced a rapid reduction of CRP levels, leading to normal levels after two weeks of treatment. Peak reduction in the absolute neutrophile count was observed after 3 to 4 days of treatment followed by a recovery to baseline levels. It is observed a decrease in fibrinogen and serum amyloid A as well as an increase in hemoglobin and serum albumin. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Sarilumab functions by: Sarilumab is a human recombinant IgG1 antibody that binds to both forms of interleukin 6 receptors (IL-6R), thus inhibiting the IL-6-mediated signaling. IL-6 is known to be a pleiotropic cytokine that activates immune cells (T and B cells), as well as hepatocytes for the release of acute phase proteins like CRP, serum amyloid A and fibrinogen which are biomarkers of RA activity. IL-6 is also found in synovial fluid and plays a major role in the pathological inflammation and joint destruction features of RA. Thus, it is used for the treatment of RA due to its ability to inhibit intra-articular and systemic IL-6 signaling . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Sarilumab 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:

Sarilumab is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antibodies, Antibodies, Monoclonal, Antineoplastic and Immunomodulating Agents, Antirheumatic Agents, Biologics for Rheumatoid Arthritis Treatment, Blood Proteins, Cytochrome P-450 CYP3A Inducers, Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 CYP3A4 Inducers, Cytochrome P-450 CYP3A4 Inducers (weak), Cytochrome P-450 CYP3A4 Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors (weak), Cytochrome P-450 Enzyme Inducers, Cytochrome P-450 Enzyme Inhibitors, Disease-modifying Antirheumatic Agents, Globulins, Immunoglobulins, Immunoproteins, Immunosuppressive Agents, Immunotherapy, Interleukin Inhibitors, Interleukin-6 Receptor Antagonist, Proteins, Serum Globulins. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Sarilumab include:

• Melting Point: 69 °C (midpoint transition), 80 °C (whole IgG1)
• Isoelectric Point: 6.6 - 7.2
• Molecular Weight: 150000.0
• Molecular Formula: C6388H9918N1718O1998S44