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General Description:

Imlifidase, identified by CAS number 1947415-68-0, is a notable compound with significant therapeutic applications. Chronic kidney disease (CKD) is a progressive and irreversible disease that represents a significant burden for both the individual and healthcare system at large. Currently available treatments for end-stage renal disease are limited to dialysis and renal transplantation, with the former associated with significant costs and lower quality of life. Patients who have developed human leukocyte antigen (HLA) sensitization from prior exposure to blood products, pregnancy, or any other circumstance which may have resulted in exposure to non-self HLA antigens, face additional barriers to transplantation. Highly sensitized individuals carry high levels of anti-HLA antibodies and are at significant risk for antibody-mediated rejection which occurs mainly through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). High levels of anti-HLA antibodies also contribute to poor graft survival. As a result, highly sensitized individuals experience marked delays on transplant lists due to the challenges associated with procuring an HLA compatible donor graft. Imlifidase is a cysteine protease and eliminates Fc-dependent effector functions such as CDC and ADCC by cleaving the heavy chains of human immunoglobulin G (IgG) antibodies. As a result, the risk of antibody-mediated rejection is reduced allowing kidney transplantation in highly sensitized patients to proceed.

Indications:

This drug is primarily indicated for: Imlifidase is indicated for desensitization of highly sensitized adult kidney transplant patients with a positive crossmatch against an available deceased donor. The treatment is reserved for patients unlikely to receive a transplant under the available kidney allocation system including prioritization programs for highly sensitized patients. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Imlifidase undergoes metabolic processing primarily in: There is currently no imlifidase metabolism data available; however, it is thought to be eliminated via proteolysis. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Imlifidase are crucial for its therapeutic efficacy: Given that imlifidase is administered intravenously, it is fully absorbed and bioavailable; imlifidase exposure is dose-proportional and predictable. After a dose of 0.25 mg/kg, the mean Cmax of imlifidase was 5.8 (4.2-8.9) ug/mL. Tmax occurs once infusion is complete or soon after. Food is not expected to impact the effectiveness or absorption of imlifidase. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Imlifidase is an important consideration for its dosing schedule: The mean distribution half-life of imlifidase is reported to be 1.8 hours, while the mean elimination half-life is reported to be 89 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Imlifidase exhibits a strong affinity for binding with plasma proteins: There is currently no evidence to suggest that imlifidase binds to any other protein besides its primary target - immunoglobulin G (IgG). Studies have demonstrated that imlifidase is highly specific for IgG and does not bind to any other human immunoglobulins. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Volume of Distribution:

Imlifidase is distributed throughout the body with a volume of distribution of: The volume of distribution of imlifidase is reported to be 0.2 L/kg in the elimination phase. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Imlifidase is a critical factor in determining its safe and effective dosage: The mean clearance value of imlifidase is reported to be 1.8 mL/h/kg. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Imlifidase exerts its therapeutic effects through: Imlifidase is highly specific to all four human IgG subclasses and does not cleave any other immunoglobulins (IgM, IgA, IgE, IgD). The inactivation of human IgG antibodies occurs rapidly and efficiently after administration of imlifidase, with the effect lasting for several weeks. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Imlifidase functions by: Imlifidase is a cysteine protease derived from _Streptococcus pyogenes_ which degrades immunoglobulin G (IgG) in a multistep process. In the first step, imlifidase cleaves one of the two IgG heavy chains at the lower hinge leaving the other intact, resulting in a single cleaved IgG molecule. In the second step, the second heavy chain is cleaved yielding one homodimeric Fc fragment and one F(ab’)₂ fragment. This process removes the ability of the F(ab’)₂ fragments to participate in Fc-mediated functions including antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Ultimately, by degrading the entire IgG pool, imlifidase reduces donor-specific antibodies (DSA) and allows transplantation to occur. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Imlifidase 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:

Imlifidase is categorized under the following therapeutic classes: Antineoplastic and Immunomodulating Agents, Endopeptidases, Immunosuppressive Agents, Immunotherapy, Selective Immunosuppressants. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Imlifidase include:

• Molecular Formula: C1575H2400N422O477S6