Dupilumab API Manufacturers

General Description:

Dupilumab, identified by CAS number 1190264-60-8, is a notable compound with significant therapeutic applications. Dupilumab is a fully human monoclonal antibody of the immunoglobulin G4 subclass that binds to the interleukin-4 (IL-4) receptor, inhibiting the receptor signaling pathways. As an interleukin-4 receptor alpha antagonist, dupilumab inhibits the signaling of pro-inflammatory cytokines, called interleukins (IL), that induce inflammatory and immunological reactions in several atopic or allergic conditions, such as eczema, allergic reaction, and rhinosinusitis. Dupilumab was generated by recombinant DNA technology in Chinese Hamster Ovary cell suspension culture. Dupilumab is commonly marketed as Dupixent, which is available as a formulation for subcutaneous injection. It was first approved by the FDA in 2017. It is currently used to treat atopic dermatitis, asthma as an add-on maintenance treatment, chronic rhinosinusitis with nasal polyposis, and eosinophilic esophagitis. It is used as monotherapy or in combination with other drugs, such as corticosteroids. Dupilumab is currently under investigations for potential therapeutic use in diseases driven by allergic reactions or type 2 inflammation, such as pediatric atopic dermatitis, and chronic obstructive pulmonary disease. It is also being studied in combination with another antibody that which targets IL-33.

Indications:

This drug is primarily indicated for: In the US, dupilumab is indicated for the treatment of patients aged six months and older with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. In Europe and Canada, the drug for this indication is approved for patients aged six years and older. In Europe, patients six to 11 years of age should have severe atopic dermatitis and be candidates for systemic therapy. Dupilumab can be used with or without topical corticosteroids for this condition. Dupilumab is indicated as an add-on maintenance treatment of patients aged six years and older with moderate-to-severe asthma characterized by an eosinophilic phenotype or with oral corticosteroid dependent asthma. However, the drug is not indicated for relief of acute bronchospasm or status asthmaticus. Dupilumab is indicated as an add-on maintenance treatment in adult patients with inadequately controlled chronic rhinosinusitis with nasal polyposis. In Canada and Europe, it is used with intranasal corticosteroids. In the US, dupilumab is also indicated for the treatment of adults and children aged 12 years and older weighing at least 40 kg with eosinophilic esophagitis (EoE), and adults with prurigo nodularis. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Dupilumab undergoes metabolic processing primarily in: Being a monoclonal antibody, dupilumab is not expected to undergo significant hepatic metabolism. While the metabolism of dupilumab has not been characterized, it is speculated that dupilumab undergoes nonspecific degradation into smaller peptides and amino acids, as often observed with endogenous IgG. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Dupilumab are crucial for its therapeutic efficacy: The Cmax following administration of a single subcutaneous dose of 600 mg or 400 mg of dupilumab were 70.1 ± 24.1 mcg/mL or 41.8 ± 12.4 mcg/mL, respectively. The Tmax ranged from 3 to 7 days following administration of a single subcutaneous dose ranging from 75 to 600 mg. Following a subcutaneous dose, the absolute bioavailability of dupilumab ranged between 61% and 64% in patients with atopic dermatitis or asthma. In clinical trials, the steady-state concentrations were reached by week 16 following the administration of 600 mg starting dose and 300 mg dose every other week. At these concentrations, the mean trough concentrations ranged from 60.3 ± 35.1 mcg/mL to 79.9 ± 41.4 mcg/mL for 300 mg dose and from 29.2 ± 18.7 to 36.5 ± 22.2 mcg/mL for 200 mg dose administered every other week. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Dupilumab is an important consideration for its dosing schedule: There is limited human data on the half-life of dupilumab. In single-dose pharmacokinetic studies, the mean half-life of dupilumab following intravenous or subcutaneous administration ranged from 4.8 to 7 days in rats and 11.7 to 20.5 days in cynomolgus monkeys. In these studies, the mean half-life was comparable was comparable following intravenous and subcutaneous administration. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Dupilumab exhibits a strong affinity for binding with plasma proteins: There is limited data on the serum protein binding profile of dupilumab. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Dupilumab from the body primarily occurs through: Being a monoclonal antibody, dupilumab is not expected to undergo significant renal elimination. It is proposed that dupilumab is eliminated via parallel linear and nonlinear pathways. At higher concentrations, dupilumab is primarily cleared through a non-saturable proteolytic pathway. At lower concentrations, it undergoes a non-linear saturable IL-4R α target-mediated elimination. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Dupilumab is distributed throughout the body with a volume of distribution of: The estimated volume of distribution is 4.8 ± 1.3 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Dupilumab is a critical factor in determining its safe and effective dosage: There is limited data on the clearance of dupilumab. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Dupilumab exerts its therapeutic effects through: Dupilumab is an recombinant human IgG4 antibody to the IL-4 receptor that works by inhibiting the activation of certain pro-inflammatory cytokines that are implicated in the pathophysiology of several allergic and atopic conditions, including asthma, chronic rhinosinusitis with nasal polyps, and food and environmental allergies. _In vivo_, dupilumab was shown to reduce the levels of type 2 inflammatory biomarkers associated with atopic dermatitis, such as thymus and activation-regulated chemokine (TARC/CCL17), total serum IgE, allergen-specific IgE, and lactate dehydrogenase (LDH). A decrease in the levels of biomarkers of asthma, such as FeNO, eotaxin-3, IgE, periostin, and eotaxin-3 (CCL26) was also observed. Since dupilumab works to suppress the immune response, it is proposed that it may influence the immune response against some infections, such as helminth infections, by inhibiting IL-4/IL-13 signaling. It is advised that infections are appropriately treated until resolved before initiating dupilumab therapy. While findings of some _in vitro_ and _in vivo_ studies suggest that some cytokine modulators may influence the expression and activity of specific cytochrome P450 (CYP450) enzymes, an open-label drug-drug interaction study demonstrated that dupilumab displays no significant effect on the activity of CYP450 enzymes studied (CYP3A, CYP2C19, CYP2C9, CYP1A2, and CYP2D6). The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Dupilumab functions by: Type 2 inflammatory processes in various allergic and atopic conditions, such as asthma and atopic diseases, involve the type 2 helper T-cell (Th2) immunity. Upregulation of this Type 2/Th2 pathway is commonly observed in other inflammatory conditions and the activation of Th2 cells is linked to the production of Th2-associated cytokines, such as interleukin (IL) 4, IL-5, IL-9, and IL-13. IL-4 and IL-13 play a central role in inducing inflammatory conditions such as allergic rhinitis, asthma, and atopic dermatitis, by regulating Type 2 inflammation and immune function. These inflammatory cytokines work by modulating gene expression downstream of receptor signalling, regulating Th2 cell differentiation, and activating inflammatory cells such as mast cells and macrophages. There are two types of receptors for IL-4: the type 1 receptor, which is composed of the IL-4 chain (IL-4Rα) and a γ chain (γC), and the type 2 receptor, which is composed of the IL-4Rα chain and the α1 chain of the IL-13 receptor (IL-13Rα1). Essentially, IL‐4Rα is a component shared by the IL‐4 and IL-13 receptor complexes and is ubiquitously expressed on both innate and adaptive immune cells to promote the signaling of IL-4 and IL-13. The type I receptor is primarily expressed on lymphocytes and controls Th2-cell differentiation, whereas the type II receptor is mostly found across resident and myeloid cells. Dupilumab is a fully human monoclonal antibody directed against IL‐4Rα to inhibit the signalling of IL‐4 and IL‐13. Dupilumab inhibits IL-4 signalling via the Type I receptor (IL-4Rα/γc), and both IL-4 and IL-13 signaling through the Type II receptor (IL-4Rα/IL-13Rα). It ultimately downregulates type-2 immunity. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Dupilumab 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:

Dupilumab is categorized under the following therapeutic classes: Agents for Dermatitis, Excluding Corticosteroids, Amino Acids, Peptides, and Proteins, Anti-Asthmatic Agents, Antibodies, Antibodies, Monoclonal, Blood Proteins, Dermatologicals, Globulins, Immunoglobulins, Immunoproteins, Interleukin 4 Receptor alpha Antagonists, Interleukin-4 Receptor alpha Antagonist, Interleukin-4 Receptor alpha Subunit, antagonists & inhibitors, Misc. Skin and Mucous Membrane Agents, 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 Dupilumab include:

• Molecular Weight: 146896.9522
• Molecular Formula: C6512H10066N1730O2052S46