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General Description:

Satralizumab, identified by CAS number 1535963-91-7, is a notable compound with significant therapeutic applications. Satralizumab is a recombinant humanized monoclonal antibody targeted against human interleukin-6 (IL-6) receptors, similar to , which is produced in Chinese hamster ovary cells and based on an IgG2 framework. Satralizumab is used in the treatment of neuromyelitis optica spectrum disorder (NMOSD), a rare autoimmune inflammatory disorder of the central nervous system (CNS) involving demyelinating lesions in the optic nerve, spinal cord, brainstem, and cerebrum. Some of the pro-inflammatory mechanisms involved in NMOSD are thought to be mediated, at least in part, by IL-6, including increased production of anti-aquaporin-4 (AQP4) autoantibodies and increased permeability of the blood-brain barrier, which allows for the passage of pro-inflammatory mediators into the CNS. Satralizumab is thought to exert its therapeutic benefits by blocking IL-6 receptors and, subsequently, these inflammatory responses. Enspryng®, a satralizumab formulation developed by Chugai Pharmaceutical and Roche, is uniquely formulated with "recycling antibody technology" whereby the association of satralizumab to IL-6 receptors occurs in a pH-dependent manner - this allows satralizumab to bind an IL-6 receptor until it reaches an endosome, after which the drug may dissociate from the receptor and move back into the plasma to act again. This novel mechanism effectively increases the duration of action of satralizumab, as it allows for single drug molecules to interact with multiple endogenous IL-6 receptors prior to elimination. Satralizumab was first approved for use in Canada in June 2020 for the treatment of AQP4 antibody-positive patients with NMOSD. It received subsequent approvals in Switzerland and Japan, and was approved for use by the FDA in August 2020, becoming the 3rd treatment to receive FDA approval for NMOSD (after in June 2019 and in June 2020).

Indications:

This drug is primarily indicated for: Satralizumab is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. In Canada, it is also used in adolescent patients for the same indication. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Satralizumab undergoes metabolic processing primarily in: While the metabolism of satralizumab has not been studied directly, monoclonal antibodies as a class are principally cleared by catabolism. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Satralizumab are crucial for its therapeutic efficacy: The C_max and AUC at steady-state, achieved after an 8-week loading period, were approximately 31.5 mcg/mL and 737 mcg.mL/day, respectively. Average C_trough concentrations were approximately 19 mcg/mL. The bioavailability of satralizumab following subcutaneous injection has been reported to be between 78.5% and 85%. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Satralizumab is an important consideration for its dosing schedule: The terminal half-life of satralizumab is approximately 30 days (range 22-37 days). This determines the duration of action and helps in formulating effective dosing regimens.

Route of Elimination:

The elimination of Satralizumab from the body primarily occurs through: Monoclonal antibodies are typically eliminated via uptake into cells and subsequent catabolism via lysosomal degradation. Due to their large size, they are only eliminated renally under pathologic conditions. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Satralizumab is distributed throughout the body with a volume of distribution of: Satralizumab is subject to biphasic distribution - the estimated volume of distribution for the central and peripheral compartments are 3.46 L and 2.07 L, respectively. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Satralizumab is a critical factor in determining its safe and effective dosage: The total clearance of satralizumab is concentration-dependent and is estimated to be 0.0601-0.0679 L/day. The inter-compartmental clearance was 0.336 L/day. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Satralizumab exerts its therapeutic effects through: Enspryng®, a satralizumab formulation developed by Chugai Pharmaceutical and Roche, utilizes a novel "recycling antibody technology" whereby the association of satralizumab to IL-6 receptors occurs in a pH-dependent manner. Satralizumab-bound IL-6 receptors are taken up into cells and transported into endosomes, a relatively acidic environment in comparison to plasma (pH 5.5-6.0 vs. pH 7.4) - this decrease in pH allows satralizumab to dissociate from the IL-6 receptor and be recycled back into the plasma, where it can bind to another IL-6 receptor and repeat the process. Satralizumab has been associated with an increased risk of infection, including serious and potentially fatal infections. It should not be administered to patients with active infections, including localized infections, until the infection resolves, and is contraindicated for use in patients with active hepatitis B or tuberculosis. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Satralizumab functions by: Interleukin-6 (IL-6) is a pro-inflammatory cytokine which has been implicated in the pathogenesis of NMOSD. The inflammatory cascade triggered by IL-6 signaling is thought to result in the differentiation of T-cells into pro-inflammatory TH17 cells and the differentiation of B-cells into plasmablasts producing AQP4 autoantibodies. IL-6 may also play a role in increasing the permeability of the blood-brain barrier, thereby allowing penetration of autoantibodies and pro-inflammatory mediators into the central nervous system. Satralizumab is a humanized monoclonal antibody targeted against human IL-6 receptors. It binds to soluble and membrane-bound IL-6 receptors and prevents the signaling cascade, and subsequent pro-inflammatory effects, associated with its binding to endogenous IL-6. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Satralizumab 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:

Satralizumab is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antibodies, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic and Immunomodulating Agents, Blood Proteins, Globulins, Immunoglobulins, Immunoproteins, Immunosuppressive Agents, 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 Satralizumab include:

• Molecular Weight: 143000.0