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General Description:

Talimogene laherparepvec, identified by CAS number 1187560-31-1, is a notable compound with significant therapeutic applications. Talimogene laherparepvec is an oncolytic treatment used in local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with recurrent melanoma. It is a genetically administered herpes simplex virus 1 (HSV-1) that expresses human cytokine granulocyte-macrophage colony stimulating factor (GM-CSF) with antitumor and immune-stimulating activities. It specifically replicates within tumor cells and causes lysis. It was approved by the FDA in 2015 under the market name Imlygic. In general, talimogene laherparepvec has been modified so that it can infect and multiply inside melanoma cells . The drug subsequently uses the melanoma cells' own machinery to multiply, eventually overwhelming the melanoma cells and killing them . Alternatively, although talimogene laherparepvec also enters healthy cells, it is not designed to multiply inside them .

Indications:

This drug is primarily indicated for: This medication is a genetically modified oncolytic viral therapy indicated for the local treatment of unresectable, cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery . Elsewhere, the EMA notes that the agent is indicated for the treatment of adults with unresectable melanoma that is regionally or distantly metastatic (Stage IIIB, IIIC, and IVM1a) with no bone, brain, lung, or other visceral diseases . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Talimogene laherparepvec undergoes metabolic processing primarily in: Talimogene laherparepvec is cleared through general host defense mechanisms like autophagy and adaptive immune responses . The agent is ultimately degraded by common endogenous protein and DNA catabolic pathways . As with other wild-type HSV-1 (herpes simplex virus type-1) infections, a latent pool of talimogene laherparepvec DNA may persist in neuronal cell bodies innervating the injection sites . Consequently, the occurrence of latent infection with talimogene laherparepvec cannot be excluded . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Talimogene laherparepvec are crucial for its therapeutic efficacy: Cellular uptake of talimogene laherparepvec occurs through HSV-1 receptors on both tumor and non-tumor cells following local injection into physical tumors . After injection, the talimogene laherparepvec subsequently replicates intratumorally, where bioavailability and systemic concentration of the agent are not largely predictive of drug substance activity and therefore such data has not been evaluated to any particular degree . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Talimogene laherparepvec is an important consideration for its dosing schedule: Readily accessible data regarding the half-life of talimogene laherparepvec is not available, although talimogene laherparepvec DNA has been found in patient subjects' injected tumor through 84 days and the half-lives of antibody-based therapeutics are often times generally long, on the order of days versus hours with small molecule drugs . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Talimogene laherparepvec exhibits a strong affinity for binding with plasma proteins: Talimogene laherparepvec is a genetically modified and replication-competent HSV-1 virus . Therefore, its pharmacokinetics and biodistribution are driven by the specific site of intralesional injection, tumor-selective replication, and release from tumor tissue . As a result, the specific pharmacokinetics of the agent, including any kind of protein binding may vary depending on particular parameters of each unique administration. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Talimogene laherparepvec from the body primarily occurs through: In an ongoing melanoma study, interim results from 30 patients show that talimogene laherparepvec DNA was detected at transient and low concentrations in blood in 90% of patients and in urine in 20% of patients in the study, which suggests that perhaps at least some portion of the drug is eliminated in the urine . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Talimogene laherparepvec is distributed throughout the body with a volume of distribution of: Talimogene laherparepvec is a genetically modified and replication-competent HSV-1 virus . Therefore, its pharmacokinetics and biodistribution are driven by the specific site of intralesional injection, tumor-selective replication, and release from tumor tissue . As a result, the specific pharmacokinetics of the agent, including distribution may vary depending on particular parameters of each unique administration. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Talimogene laherparepvec is a critical factor in determining its safe and effective dosage: Although readily accessible data regarding the clearance of talimogene laherparepvec is not available, in an ongoing melanoma study, it was determined that the proportion of patients with detectable talimogene laherparepvec DNA in blood and urine was highest during the second cycle of therapy . Additionally, even though talimogene laherparepvec DNA was detected in samples from injected lesions in about 90% of patients, only 14% of patients tested positive for infective virus by 50% Tissue Culture Infectious Dose (TCID50) assay, all within 8 days of treatment administration . 17% of samples from the exterior occlusive dressing tested positive for talimogene laherparepvec DNA but none tested positive for the presence of infective virus . Moreover, only 1 sample had detectable talimogene laherparepvec DNA located on the oral mucosa - but the sample did not test positive for the presence of infective virus . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Talimogene laherparepvec exerts its therapeutic effects through: Talimogene laherparepvec has been genetically modified to replicate within tumors and to produce the immune stimulatory protein GM-CSF (granulocyte macrophage colony stimulating factor) . The medication causes lysis of tumors, followed by the release of tumor-derived antigens, which together with virally derived GM-CSF may promote an anti-tumor immune response in the body . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Talimogene laherparepvec functions by: Talimogene laherparepvec is an oncolytic immunotherapy that is derived from Herpes Simplex Virus type-1 (HSV-1) . It has been modified to replicate within tumor cells and to produce the immune response stimulatory protein, human GM-CSF (granulocyte macrophage colony stimulating factor) . The medication causes the death of tumor cells and the release of tumor-derived antigens . It is believed that together with GM-CSF, talimogene laherparepvec can promote a systemic anti-tumor immune response and an effector T-cell response . Mice subjects involved in talimogene laherparepvec treatment studies that had complete regression of their primary tumors following therapy were resistant to subsequent tumor rechallenge . The genetic modifications to talimogene laherparepvec from HSV-1 include deletion of the ICP34.5 and ICP47 genes . Whereas anti-viral immune responses defend normal cells following infection by talimogene laherparepvec, tumors have been shown to be susceptible to injury and cell death from ICP34.5-deficient HSV-1 derived viruses, including talimogene laherparepvec . Moreover, deletion of ICP47 prevents the down-regulation of antigen presentation molecules in the targeted tumor cells and increases the expression of the HSV US11 gene, thereby enhancing the talimogene laherparepvec viral replication in tumor cells and increases chances of tumor cell injury and death . Although the talimogene laherparepvec virus is specifically modified to infect and multiply inside melanoma cells and uses melanoma cells' own machinery to multiply, the medication is not designed to multiply inside healthy cells, which it is also capable of entering . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Talimogene laherparepvec 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:

Talimogene laherparepvec is categorized under the following therapeutic classes: Alphaherpesvirinae, Antineoplastic Agents, Antineoplastic Agents, Immunological, Antineoplastic and Immunomodulating Agents, Cancer immunotherapy, Complex Mixtures, DNA Viruses, Herpesviridae, Immunotherapy, Simplexvirus, Viruses. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.