Durvalumab API Manufacturers

General Description:

Durvalumab, identified by CAS number 1428935-60-7, is a notable compound with significant therapeutic applications. Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody and a novel immune-checkpoint inhibitor for cancer treatment. Produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cell suspension culture, durvalumab is a programmed death-ligand 1 (PD-L1) blocking antibody that works to promote normal immune responses that attack tumour cells. Durvalumab is marketed under the brand name Imfinzi, which is available for intravenous injections. It was granted accelerated approval by the FDA in May 2017 for the treatment of selected patients with locally advanced or metastatic urothelial carcinoma. In September 2018, durvalumab was approved by the EMA for the treatment of adult patients with locally advanced, unresectable non-small cell lung cancer (NSCLC), only if PD-L1 is expressed in ≥ 1% of tumour cells and there was no observable disease progression following platinum-based chemoradiation therapy. On March 27, 2020, durvalumab was approved by the FDA for use in combination with and either or as first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC).

Indications:

This drug is primarily indicated for: Durvalumab is indicated for the treatment of adults with the following conditions: - unresectable Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. - metastatic NSCLC with no sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) genomic tumour aberrations, in combination with and platinum-based chemotherapy. - extensive-stage small cell lung cancer (ES-SCLC) in combination with and either or as first-line therapy. - locally advanced or metastatic biliary tract cancer (BTC) in combination with and cisplatin. - unresectable hepatocellular carcinoma (uHCC) in combination with . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Durvalumab undergoes metabolic processing primarily in: Durvalumab is subject to protein catabolism via reticuloedothelial system or target-mediated disposition. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Durvalumab are crucial for its therapeutic efficacy: Durvalumab exhibits a dose-proportional pharmacokinetic profile that is non-linear at doses <3 mg/kg and linear at doses ≥3 mg/kg. Following intravenous administration in patients with solid tumours, the steady-state plasma concentrations were reached at approximately 16 weeks. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Durvalumab is an important consideration for its dosing schedule: Based on baseline clearance rate, the geometric mean terminal half-life is 18 days. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

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

Route of Elimination:

The elimination of Durvalumab from the body primarily occurs through: Durvalumab is primarily eliminated by protein catabolism. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Durvalumab is distributed throughout the body with a volume of distribution of: In patients receiving the dose range of ≥ 10 mg/kg every 2 weeks, the mean steady state volume of distribution (Vss) was 5.64 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Durvalumab is a critical factor in determining its safe and effective dosage: Clearance of durvalumab decreases over time, resulting in a mean steady-state clearance (CLss) of 8.2 mL/h following 365 days of initial drug administration. However, the decrease in CLss is not considered clinically relevant. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Durvalumab exerts its therapeutic effects through: Durvalumab is an anticancer antibody that works to promote the antitumour responses mediated by immune cells. By blocking the action of PD-L1, durvalumab exerts its anticancer effects by increasing T-cell activation, enhancing detection and ablation of tumour cells. In _in vitro_ assays, durvalumab inhibited the activity of PD-L1 in a concentration-dependent manner. In co-engrafted human tumor and immune cell xenograft mouse models, durvalumab was effective in decreasing tumour size. Durvalumab does not mediate antibody-dependent cell-mediated cytotoxicity (ADCC). The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Durvalumab functions by: Because cancer cells express antigens that are recognized and taken up by antigen-presenting cells (APCs), the immune responses prime and activate cytotoxic T cells, and allow them to travel to the site of the tumour to destroy cancer cells. However, tumours often evade T cell-mediated immune responses to enhance their survival. Inflammatory mediators, such as IFN-gamma, induce the expression of programmed cell death ligand-1 (PD-L1), which is a type 1 transmembrane protein expressed on tumour cells and tumour-associated immune cells in the tumour microenvironment. PD-L1 acts as an immune checkpoint to regulate immune responses. PD-L1 is a ligand to PD-1, which is a cell surface receptor expressed on activated T cells in peripheral tissues following antigen exposure. Both PD-L1 and PD-1 are co-inhibitory molecules involved in blocking T cell-mediated immune responses. PD-L1 also interacts with CD-80, which is a receptor constitutively expressed by T cells and is upregulated early after T cell activation. The expression of PD-L1 is an adaptive immune response by tumour cells, resulting in the over-expression of the molecule in some cancers. PD-L1 interacts with PD-1 and CD80, which leads to blocked cytotoxic T cell activation, T cell proliferation, and cytokine production. By binding to PD-L1 and preventing its association with PD-1 and CD80, durvalumab activates the immune responses mediated by cytotoxic T cells that attack tumour cells. Durvalumab displays selective and high affinity toward PD-L1 but not PD-L2, which is a regulatory ligand expressed in tumour cells to a lesser extent and involved in regulating inflammation and differentiation of T cells. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Durvalumab 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:

Durvalumab is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antibiotics, Antineoplastic, Antibodies, Antibodies, Monoclonal, Antineoplastic Agents, Antineoplastic Agents, Immunological, Antineoplastic and Immunomodulating Agents, Blood Proteins, Cancer immunotherapy, Globulins, Immune Checkpoint Inhibitors, Immunoglobulins, Immunoproteins, Immunotherapy, MONOCLONAL ANTIBODIES AND ANTIBODY DRUG CONJUGATES, Narrow Therapeutic Index Drugs, PD-1/PDL-1 (Programmed cell death protein 1/death ligand 1) inhibitors, Programmed Death Ligand-1 Antagonists, Programmed Death Ligand-1 Blocker, Programmed Death Ligand-1-directed Antibody Interactions, 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 Durvalumab include:

• Molecular Weight: 146300.0
• Molecular Formula: C6502H10018N1742O2024S42