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General Description:

Etrolizumab, identified by CAS number 1044758-60-2, is a notable compound with significant therapeutic applications. Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is typified by a chronic gastrointestinal inflammatory microenvironment, driven in part by the excessive infiltration and retention of intestinal-homing lymphocytes. A recent class of drugs designed to impair lymphocyte homing, so-called "anti-trafficking agents" (ATAs), have shown some success and include approved drugs such as and , which target integrins and impair their interaction with adhesion molecules on epithelial cells. In the case of , which targets the α4 integrin subunit, this has also resulted in undesirable blockade of lymphocyte CNS trafficking and reported cases of progressive multifocal leukoencephalopathy (PML). Etrolizumab is a humanized IgG1κ monoclonal antibody directed against the β7 subunit of gastrointestinal α4β7 and αEβ7 integrins that, due to its target specificity, appears as or more efficacious than and without the CNS effects of . Etrolizumab is currently under investigation for the treatment of ulcerative colitis and Crohn's disease.

Metabolism:

Etrolizumab undergoes metabolic processing primarily in: Etrolizumab, as a monoclonal antibody, is expected to undergo proteolytic degradation in multiple locations throughout the body. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Etrolizumab are crucial for its therapeutic efficacy: Etrolizumab administered as a single 105 mg subcutaneous injection by prefilled syringe or autoinjector device in healthy adults aged 18-55 resulted in a geometric mean (%CV) C_max of 12.2-12.5 μg/mL (28.3-32.0), AUC_last of 319-325 μg\*day/mL (33.1-35.3), and AUC_0-∞ of 329-337 μg\*day/mL (35.2-36.0). The median time to maximum serum concentration (T_max) was 5.04 days (range 2.98-14.0) for the autoinjector and 6.97 days (range 3.00-14.0) for the syringe. Studies in adult patients with ulcerative colitis revealed approximately linear pharmacokinetics at doses >1.0 mg/kg and an accumulation ratio over three doses (four weeks apart) of 1.2-fold for intravenous dosing and 2.0-fold for subcutaneous dosing. The apparent bioavailability of subcutaneous etrolizumab was estimated at 67% at the 3 mg/kg level. Etrolizumab pharmacokinetics were also evaluated in pediatric patients aged 4-17 years with moderately to severely active ulcerative colitis or Crohn's disease given either 1.5 mg/kg etrolizumab every four weeks (q4w) for four doses or 3.0 mg/kg every eight weeks (q8w) for two doses by subcutaneous injection. The 1.5 mg/kg dose resulted in a mean C_max of 7.7 ± 2.18 μg/mL after the first dose and 9.8 ± 4.86 μg/mL after the last dose and an AUC_84-112d of 167 ± 86.9 μg\*day/mL. The 3.0 mg/kg dose resulted in a mean C_max of 19.0 ± 8.21 μg/mL after the first dose and 18.1 ± 6.25 μg/mL after the last dose and an AUC_56-112d of 521 ± 306 μg\*day/mL. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Etrolizumab is an important consideration for its dosing schedule: Etrolizumab administered as a single 105 mg subcutaneous injection by prefilled syringe or autoinjector device in healthy adults aged 18-55 resulted in a similar mean half-life of 11.8 ± 3.85 days for the injector and 12.2 ± 4.39 days for the syringe. In adult ulcerative colitis patients, the half-life was similar at higher doses (10.6-13.1 days for 3-10 mg/kg) but shorter at smaller doses (4.8-7.4 days at 0.3-1.0 mg/kg). The half-life in pediatric patients was similar at 7.3 ± 1.76 days at the 1.5 mg/kg q4w level and 8.7 ± 3.74 at the 3.0 mg/kg q8w level. This determines the duration of action and helps in formulating effective dosing regimens.

Volume of Distribution:

Etrolizumab is distributed throughout the body with a volume of distribution of: Modelling of etrolizumab pharmacokinetic data from adult patients with moderate to severe ulcerative colitis yielded a central volume of distribution of either 2570 mL (from the quasi-steady-state target-mediated drug disposition model) or 3200 mL (from the linear model). Subcutaneous administration of either 1.5 mg/kg q4w or 3.0 mg/kg q8w etrolizumab in pediatric patients with ulcerative colitis or Crohn's disease yielded an apparent volume of distribution of 4920 ± 2440 mL and 3910 ± 1830 mL, respectively. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Etrolizumab is a critical factor in determining its safe and effective dosage: Etrolizumab has a mean clearance in adult patients of ~300 mL/day, which appears higher in pediatric patients (385-505 mL/day). It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Etrolizumab exerts its therapeutic effects through: Etrolizumab is a humanized anti-β7 integrin subunit monoclonal antibody that impairs the targeting and retention of gut-specific lymphocytes contributing to an inflammatory microenvironment in ulcerative colitis and Crohn's disease. Studies in cynomolgus monkeys demonstrate that etrolizumab specifically increases the number of circulating β7^high lymphocytes without significantly altering other lymphocyte populations. This is in good agreement with the observed β7 occupancy by etrolizumab in animal models and human blood samples during clinical trials. Early studies in mice and cynomolgus monkeys suggested etrolizumab serum concentrations of 1-10 μg/mL were required to maintain β7 saturation; data from human clinical studies revealed an EC₉₀ for β7 occupancy of 1.3 μg/mL, and serum concentrations in the range of 1-3 μg/mL demonstrated complete or near-complete β7 saturation in adult and pediatric patients. Unlike , which binds α4 integrin and hence disrupts the α4β1:VCAM-1 interactions required for CNS immune cell homing, there have been no associations thus far between etrolizumab and progressive multifocal leukoencephalopathy (PML). The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Etrolizumab functions by: Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is characterized by chronic inflammation of the gastrointestinal tract. This inflammation is driven, at least in part, by excessive infiltration and retention of intestinal-homing lymphocytes. An adhesion cascade drives the infiltration of immune cells. The binding of immune cell glycoproteins to their corresponding epithelial cell selectins results in partial retention and the "rolling" of immune cells along the endothelium. A stable arrest is mediated by stronger interactions between immune cell integrins and cell adhesion molecules (CAMs) on the endothelial cell; once arrested, immune cells will extravasate and enter the target tissue. Tissue retention is mediated by similar interactions between cell-surface molecules within the target tissue, which impedes immune cells' re-entry into the systemic circulation. Integrins are heterodimeric cell-surface receptors comprising transmembrane α and β subunits, of which multiple forms exist. Integrins primarily interact with CAMs, which are cell-surface members of the immunoglobulin superfamily expressed on vascular endothelial cells. Of primary importance to intestinal homing is the mucosal addressin cellular adhesion molecule (MAdCAM-1), which interacts strongly with α4β7 integrins, and vascular cell adhesion molecule (VCAM-1), which binds with lower affinity. MAdCAM-1 also binds to the CS-1 fragment of the extracellular matrix molecule fibronectin. α4β7 integrin is expressed at high levels on intestinal-homing lymphocytes but can also be found on natural killer cells, basophils, eosinophils, macrophages, activated monocytes, and mast cells. Another β7-containing integrin, αEβ7, is primarily expressed by lymphocytes, dendritic cells, mast cells, and innate lymphoid cells within the mucosal immune system, including the respiratory, gastrointestinal, and urogenital tracts, where it interacts with E-cadherin on mucosal tissue cells. The infiltration and retention of immune cells as a mechanism of IBD is suggested by observations across multiple studies of an increase in the number of, and alteration in the secreted cytokine profile of, α4β7⁺ and αEβ7⁺ immune cells in the gastrointestinal tract of IBD patients. These observations mirror an increase in the expression of the relevant CAMs, MAdCAM-1 and E-cadherin, in these patients. Although the mechanism has not been completely elucidated, it is clear that an increase in the number and retention of gut-homing immune cells capable of sustaining an inflammatory microenvironment is a crucial element of IBD pathophysiology. Etrolizumab is a humanized monoclonal antibody specific for the β7 integrin subunit; it has a K_d of 116 ± 11 pmol/L against human α4β7 and 1800 ± 170 pmol/L against human αEβ7, as assessed by transfection in HEK293 cells. This strong binding provides efficient inhibition of integrin/CAM interactions. Etrolizumab has an IC₅₀ for the α4β7 interactions with MAdCAM-1, VCAM-1, and fibronectin of 0.075 ± 0.034, 0.089 ± 0.009, and 0.119 ± 0.056 nmol/L, respectively. Etrolizumab also inhibits the interaction of αEβ7 with E-cadherin, albeit less effectively (IC₅₀ of 3.96 ± 1.78 nmol/L). While etrolizumab does not exhibit antibody-dependent cytotoxicity, it disrupts the integrin-CAM interactions involved in gut immune cell residence, in part by inducing the endocytic uptake of bound integrin receptors, and therefore reduces the inflammatory burden in IBD. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Classification:

Etrolizumab 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:

Etrolizumab is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antibodies, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Blood Proteins, Gastrointestinal Agents, Globulins, Immunoglobulins, Immunologic Factors, Immunoproteins, Integrin Receptor Antagonist, Proteins, Serum Globulins. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.