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General Description:

Besilesomab, identified by CAS number 537694-98-7, is a notable compound with significant therapeutic applications. Besilesomab is a mouse monoclonal antibody labelled with the radioactive isotope technetium-99m for determining the location of inflammation/infection in peripheral bone in adults with suspected osteomyelitis . Utilised only as a diagnostic agent, besilesomab is currently approved by the EMEA for marketing and use in various European countries like Italy, France, Germany, Spain, Portugal, Norway, Sweden, the Netherlands, and the United Kingdom .

Indications:

This drug is primarily indicated for: Besilesomab is radiolabelled with sodium pertechnetate (Tc99m) solution to develop technetium (Tc99m) besilesomab solution. This solution is indicated in adults for scintigraphic imaging - in conjunction with other appropriate imaging modalities, when possible - in determining the location of inflammation/infection in peripheral bone in adults with suspected osteomyelitis . When utilized as such, this medicinal product is for diagnostic use only . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Besilesomab undergoes metabolic processing primarily in: The besilesomab antibody is mainly metabolized via hepatic clearance into amino acids . Nevertheless, liver uptake of radioactivity was observed to be minimal under trial conditions and liver impairment is considered unlikely to affect besilesomab metabolism and elimination in any clinically significant manner . The total blood radioactivity occurring from the administration of besilesomab is generally the result of the contribution of radioactive intact labelled antibody and other radioactive moieties like metabolized antibody fragments, smaller radiometabolites, and free technetium (Tc99m) . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Besilesomab are crucial for its therapeutic efficacy: As the diagnostic agent is administered intravenously, it is expected that the bioavailability is 100% . Approximately six hours after injection, about 1.5% of the whole body radioactivity is detected in the liver while about 3.0% is found in the spleen . Observations twenty-four hours after injection demonstrate percentages of radioactivity of 1.6% in the liver and 2.3% in the spleen . However, non pathological, unusual accumulations of the radioactive agent can be detected in the spleen (up to 6% of patients), in the bowel (up to 4% of patients), in the liver and bone marrow (up to 3% of patients), and in the thyroid and kidneys (up to 2% of patients) . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Besilesomab is an important consideration for its dosing schedule: Whole blood concentration-time radioactivity curves show a two-phase course, which can be subdivided into an early phase (0-2 h) and a late phase (5-24 h) . After correcting for the decay of radionuclide, the calculated half-life of the early phase is approximately 0.5 h while the late phase demonstrates a calculated half-life of 16 h . The terminal half-life in man is estimated to be approximately 23 h . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Besilesomab exhibits a strong affinity for binding with plasma proteins: Studies demonstrate that prepared kit besilesomab binds up to 97.45% and 96.58% of peripheral blood granulocytes in males and females respectively and less than 5% of other peripheral blood cells . Moreover, no significant binding of the antibody to other human peripheral blood cells like erythrocytes, platelets, lymphocytes, and monocytes was observed . As well, besilesomab demonstrates no cross-reactivity with human platelets . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Besilesomab from the body primarily occurs through: Measurement of radioactivity levels in urine shows that up to 14% of the administered activity is excreted via the bladder during the 24 h post-injection period. Low renal clearance activity (of 0.2 L/h for a glomerular filtration rate of approximately 7 L/h) also suggests that the kidney is not the primary route of besilesomab elimination . Additionally, over 30 hours rat pharmacokinetic studies also similarly demonstrated that 31-34% of the radioactivity was excreted in the urine and only 7-13% in the faeces . The faecal elimination was observed primarily from the 17h time period onward . Furthermore, while radioactivity associated with intact antibody tends to stay in the vascular compartment for a long time, metabolized radioactive fragments, small radio-metabolites, and free pertechnetate (Tc99m) clears quickly from blood and will accumulate in the kidneys and further in the urine . In all besilesomab studies to date, approximately 14% of the injected radioactivity was recovered in the urine, which was only collected for 24 hours after administration . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Besilesomab is distributed throughout the body with a volume of distribution of: In the besilesomab clinical trial Study 7D-101SZ-A, volumes of distribution were determined as approximately 4L - which was close to the plasma volume - in the central compartment, whether calculated from plasma radioactivity or from intact monoclonal antibody concentrations; the peripheral compartment was somewhat greater, at about 6L for both methods . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Besilesomab is a critical factor in determining its safe and effective dosage: Once administered into the body, prepared technetium (Tc99m) besilesomab can be metabolized into free amino acids, smaller radioactive fragments, or even free pertechnetate (Tc99m) . The besilesomab clinical study 7D-101SZ-A consequently reports separate estimated clearance rates of 0.322 L/h and 0.242 L/h that were calculated using monitored plasma radioactivity and from monitored intact monoclonal antibody concentrations, respectively . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Besilesomab exerts its therapeutic effects through: In a study employing cryo-preserved human tissues using an indirect alkaline phosphatase anti-alkaline phosphatase technique, besilesomab antibody from hybridoma supernatants demonstrated staining to cytoplasmic, membranous, and interstitial areas of primary colon carcinoma tissue, to single granulocytic cells in normal human liver and lung and to a large proportion of granulocytic cells in normal human bone marrow but not to blood vessels or connective tissue . Additionally, the antibody also shows binding to the granulocytic cells of breast, kidney, parotid gland, pituitary, lymph nodes, and spleen tissues, as well as colonic, pancreatic, and some lung and breast carcinomas . The purified besilesomab antibody and the prepared kit subsequently bound similarly to granulocytes in normal bone marrow, lung, liver, spleen, and colorectal carcinomas. Furthermore, the prepared kit also produced some staining in some connective tissue fibres in normal lung, some muscle fibres in normal colon, and in liver parenchymal cells . In general however, besilesomab does not bind significantly to blood vessels and connective tissue . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Besilesomab functions by: Nonspecific cross-reacting antigens (NCA) is the name of a collection of highly glycosylated bacterial binding receptors expressed on human granulocytes and other tissues . In particular, these glycoprotein receptors are members of the immunoglobulin supergene family and are related structurally to carcinoembryonic antigen (CEA) . CEA is found naturally in the human body and its expression may be increased in both cancer and non-cancerous (benign) circumstances. Besilesomab is subsequently a murine immunoglobulin monoclonal antibody of IgG1 isotype designed to recognise and bind specifically to NCA-95, or nonspecific cross-reacting antigen 95, an epitope found expressed on the cell membranes of granulocytes and granulocyte precursors . When radiolabelled with sodium pertechnetate (Tc99m) solution to develop technetium (Tc99m) besilesomab solution, this radiolabelled medicine is injected into patients where the monoclonal antibody carries it to target CEA on target granulocytes . When large numbers of CEA expressing granulocytes gather to the site of an infection, the radioactive monoclonal antibodies will also accumulate at such sites, where it can be detected by diagnostic scanning . The resultant images show where the radioactive besilesomab has accumulated, locating areas affected by osteomyelitis, infection, or inflammation . Furthermore, it is believed that the besilesomab accumulation is predominantly passive (via increased vascular permeability) and only partially active (via migration of human granulocytes carrying besilesomab to the infection/inflammation location) since only 10% to 20% of the injected radio-diagnostic agent binds in vivo to human circulating granulocytes . Specific binding of besilesomab to activated granulocytes that have already migrated to sites of infection/inflammation might be the primary part of the detection signal . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Besilesomab 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:

Besilesomab is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antibodies, Antibodies, Monoclonal, Blood Proteins, Globulins, Immunoglobulins, Immunoproteins, Proteins, Radiopharmaceuticals, Serum Globulins. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.