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General Description:

Ravulizumab, identified by CAS number 1803171-55-2, is a notable compound with significant therapeutic applications. Ravulizumab is a potent and selective complement 5 (C5) inhibitor. It is a humanized monoclonal IgG2/4 kappa antibody produced in Chinese hamster ovary (CHO) cells. Ravulizumab was engineered from , another complement inhibitor, to increase the duration of action and reduce the frequency of drug administration. It works by blocking terminal complement-mediated inflammation, cell activation, and cell lysis in blood disorders associated with the destruction of red blood cells, thrombosis, and impaired bone marrow function. Ravulizumab was first approved by the FDA on December 21, 2018, for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome in children and adults. It was later approved by the European Commission on July 2, 2019, for the same indications. Ravulizumab is also used to treat myasthenia gravis. Ravulizumab is currently being investigated for the treatment of Coronavirus disease (COVID-19)-induced microvasculature injury and endothelial damage leading to thrombotic microangiopathy (TMA) causing acute kidney injury (AKI).

Indications:

This drug is primarily indicated for: Ravulizumab is indicated for the treatment of adult and pediatric patients one month of age and older with paroxysmal nocturnal hemoglobinuria (PNH). It is also indicated for the treatment of adult and pediatric patients one month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA). However, the FDA advises against the use of ravulizumab for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). Ravulizumab is also indicated for treatment of adult patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody-positive. The European Commission approved ravulizumab for the treatment of paroxysmal nocturnal haemoglobinuria (PNH) in adults and children with a body weight of 10 kg or more with the following conditions: hemolysis with clinical symptoms indicative of high disease activity or clinically stable after having been treated with eculizumab for at least the past six months. Ravulizumab is also indicated for the treatment of hemolytic uremic syndrome (aHUS) in patients with a body weight of 10 kg or more who are either complement inhibitor treatment-naïve or have received for at least 3 months and have evidence of response to eculizumab. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Ravulizumab undergoes metabolic processing primarily in: Ravulizumab is expected to be metabolized in the same manner as any endogenous immunoglobulin gamma monoclonal antibody: it undergoes degradation into small peptides and amino acids via catabolic pathways. Ravulizumab contains only natural occurring amino acids and has no known active metabolites. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Ravulizumab are crucial for its therapeutic efficacy: In children with paroxysmal nocturnal hemoglobinuria who are complement inhibitor-naïve, the mean C_max was 733 mcg/mL following the loading dose and 1490 mcg/mL following the maintenance dose. In children who were previously treated with eculizumab, the mean C_max was 885 mcg/mL following the loading dose and 1705 mcg/mL following the maintenance dose. In adults with paroxysmal nocturnal hemoglobinuria who are complement inhibitor-naïve, the mean C_max was 771 mcg/mL following the loading dose and 1379 mcg/mL following the maintenance dose. In adults who were previously treated with eculizumab, the mean C_max was 843 mcg/mL following the loading dose and 1386 mcg/mL following the maintenance dose. In children with atypical hemolytic uremic syndrome and a body weight of less than 20 kg, the mean C_max was 656 mcg/mL following the loading dose and 1467 mcg/mL following the maintenance dose. In children with a body weight ranging from 20 to 40 kg, the mean C_max was 600 mcg/mL following the loading dose and 1863 mcg/mL following the maintenance dose. In adults with a body weight greater than 40 kg, the mean C_max was 754 mcg/mL following the loading dose and 1458 mcg/mL following the maintenance dose. T_max is expected at the end of infusion (EOI) or soon after EOI. Therapeutic steady-state drug concentrations are reached after the first dose. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Ravulizumab is an important consideration for its dosing schedule: The mean (%CV) terminal elimination half-life of ravulizumab is 49.6 (18.3) days in patients with paroxysmal nocturnal hemoglobinuria and 51.8 (31.3) days in patients with atypical hemolytic uremic syndrome. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Ravulizumab exhibits a strong affinity for binding with plasma proteins: There is no information on the protein binding of ravulizumab. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Ravulizumab from the body primarily occurs through: There is no information on the route of elimination of ravulizumab. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Ravulizumab is distributed throughout the body with a volume of distribution of: The mean (%CV) volume of distribution at steady state was 5.30 (17.9) L in patients with paroxysmal nocturnal hemoglobinuria and 5.22 (35.4) L in patients with atypical hemolytic uremic syndrome. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Ravulizumab is a critical factor in determining its safe and effective dosage: The mean (%CV) clearance of ravulizumab is 0.08 (28.1) L/day in patients with paroxysmal nocturnal hemoglobinuria and 0.08 (53.3) L/day in patients with atypical hemolytic uremic syndrome. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Ravulizumab exerts its therapeutic effects through: Ravulizumab is a potent long-acting complement inhibitor of C5, which is a key complement protein involved in inflammatory and thrombotic pathways. It has a long duration of action and fast onset of action. In a clinical study of adult and pediatric patients with paroxysmal nocturnal hemoglobinuria, completion inhibition of free C5 - determined as the serum concentration of less than 0.5 mcg/mL - was observed by the end of the first ravulizumab infusion: this effect was sustained throughout the entire 26-week treatment period. In patients with atypical hemolytic uremic syndrome, inhibition of C5 was observed in 93% of the patients in the study. C5 inhibition by ravulizumab is exposure-dependent. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Ravulizumab functions by: Complement system activation plays an important role in innate and acquired immunity. Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disorder characterized by hemolytic anemia, bone marrow failure, and thrombosis. It is caused by a genetic mutation, leading to complement-mediated hemolysis and deficiencies in glycosylphosphatidylinositol (GPI)-linked proteins such as those involved in fibrinolysis. Atypical hemolytic uraemic syndrome (aHUS) is a type of thrombotic microangiopathy also caused by complement dysregulation. It is associated with thrombocytopenia, microangiopathic hemolytic anemia, and end-organ damage. Myasthenia gravis, an autoimmune neuromuscular disease, also involves the immune system aberrantly attacking the muscles, causing progressive muscle damage. Ravulizumab inhibits the terminal complement pathway by binding to C5 with high affinity: this inhibits the cleavage of C5 to C5a, which is a pro-inflammatory and pro-thrombotic anaphylatoxin, and C5b, an initiating subunit of the terminal complement complex (C5b-9), which promotes cell lysis. Since the generation of C5b is blocked, the formation of C5b-9 is also inhibited by ravulizumab. Ravulizumab inhibits terminal complement-mediated intravascular hemolysis in patients with PNH and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. By blocking the complement system, ravulizumab ameliorates the extent of inflammatory and immune responses that play a role in the pathophysiology of myasthenia gravis. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Ravulizumab 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:

Ravulizumab is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antibodies, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic and Immunomodulating Agents, Blood Proteins, Complement Inactivating Agents, Complement Inactivator Proteins, Globulins, Immunoglobulins, Immunologic Factors, Immunoproteins, Immunosuppressive Agents, Immunotherapy, Proteins, Selective Immunosuppressants, 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 Ravulizumab include:

• Molecular Weight: 148000.0
• Molecular Formula: C6430H9888N1696O2028S48