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General Description:

Emicizumab, identified by CAS number 1610943-06-0, is a notable compound with significant therapeutic applications. Emicizumab is a humanized recombinant monoclonal antibody that mimics the function of the coagulation Factor VIII and it has the capacity to bind simultaneously to activated Factor IX and Factor X. The ability of Emicizumab to bind to all these three different factors allows it to overcome immunogenicity and unstable hemostatic efficacy produced by previous Factor VII agents. Emicizumab was originated as an improved form of hBS23 and it was approved on November 16, 2017. It was created by Chugai Pharmaceuticals Co. Ltd. and co-developed with Roche and Genentech.

Indications:

This drug is primarily indicated for: The main function of Emicizumab is the prevention of bleeding episodes. Thus, Emicizumab is approved for the routine prophylaxis to prevent or reduce the frequency of bleeding episodes of adult and pediatric patients with hemophilia A with or without Factor VIII inhibitors. Hemophilia A is a deficiency of coagulation Factor VIII which causes a serious bleeding disorder. The standard treatment is done with the administration of recombinant or serum-deriver Factor VIII which induces the formation of anti-factor VIII alloantibodies (Factor VIII inhibitors) and renders the standard treatment ineffective. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Emicizumab undergoes metabolic processing primarily in: Emicizumab is a monoclonal antibody and thus, it is thought to be internalized in endothelial cells bound to Fc receptor and rescued from metabolism by recycling. Later, they are degraded in the reticuloendothelial system to small peptides and amino acids which can be used for de-novo protein synthesis. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Emicizumab are crucial for its therapeutic efficacy: Subcutaneous administration of Emicizumab presents a very high bioavailability ranging from 80.4% to 93.1% when administered subcutaneously in a dose of 1 mg/kg. In clinical trials, at the same dose, Emicizumab presented a linear exposure which concentration peaked 1-2 weeks after administration and presented a profile framed by a Cmax of 5.92 mcg/ml and an AUC of 304 mcg day/ml. After subcutaneous administration, the absorption half-life was 1.7 days and the pharmacokinetic profile seemed to be shared when the medication was administered in the abdomen, upper arm, and thigh. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Emicizumab is an important consideration for its dosing schedule: Emcicizumab presents a long half-life ranging from 27.8 to 34.4 days. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Emicizumab exhibits a strong affinity for binding with plasma proteins: As emicizumab is a monoclonal antibody acting on the bloodstream, the determination of protein binding studies is not required. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Emicizumab from the body primarily occurs through: The elimination of Emicizumab was monophasic in clinical trials. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Emicizumab is distributed throughout the body with a volume of distribution of: The apparent volume of distribution is 11.4 L when administered subcutaneously and there are reports indicating that this value can increase with increasing body weight. When emicizumab is administered intravenously, the volume of distribution at steady state is 106 ml/kg. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Emicizumab is a critical factor in determining its safe and effective dosage: The apparent clearance is 0.24 L/day when administered in multiple subcutaneous injections and there are reports indicating that this value can increase with increasing body weight. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Emicizumab exerts its therapeutic effects through: Emicizumab mimics the function of coagulation factor VIII, therefore it binds to the activated form of Factor IX (Factor IXa). This binding forms a complex that will later bind to the X factor of the coagulation factor. The ability of Emicizumab to interact with both factors (Factor IXa and Factor X) activates the coagulation cascade that will subsequently lead to the segmentation of fibrinogen into fibrin and the formation of blood clots. The effect of Emicizumab is translated into the restoration of the blood coagulation process and, therefore, in the reduction of hemorrhagic episodes. The activity of emicizumab can also produce changes in activated clotting time (ACT), activated partial thromboplastin time (aPTT) and one-step Factor VIII activity. In addition, the unique bispecific structure of Emicizumab prevents the formation of Factor VIII inhibitors or their effect. In the first clinical trials, emicizumab was tried on previously treated adult and pediatric patients of hemophilia A with FVIII inhibitors. In this trials, the annualized bleeding rate requiring treatment with coagulation factors was reduced by 87% when compared to untreated patients. Those clinical trials were followed by a second round on previously treated patients of severe hemophilia A without FVIII inhibitors. In this trial, the annualized bleed rate was reduced by 96% when compared to untreated patients. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Emicizumab functions by: Emicizumab exerts its action by performing the function of the coagulation Factor VIII without presenting a structural homology. It presents a dual specificity which allows it to bind to both the Factor IXa and Factor X, performing the required bridging activity for the launch of the coagulation cascade. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Emicizumab 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:

Emicizumab is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antibodies, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antihemorrhagic Agents, Miscellaneous, Blood and Blood Forming Organs, Blood Coagulation Factors, Blood Proteins, Globulins, Hemostatics, Immunoglobulins, Immunoproteins, 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 Emicizumab include:

• Water Solubility: 50 mg/ml
• Melting Point: 78ºC
• Boiling Point: Fab and Fc domains denaturates at 60 and 70 ºC respectively
• Isoelectric Point: 6.6 - 7.2
• Molecular Weight: 145637.0
• Molecular Formula: C6434-H9940-N1724-O2047-S45