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General Description:

Tecovirimat, identified by CAS number 869572-92-9, is a notable compound with significant therapeutic applications. The World Health Organization declared smallpox, a contagious and sometimes fatal infectious disease, eradicated in 1980. However, there have been longstanding concerns that smallpox may be used as a bioweapon. Tecovirimat is an antiviral drug that was identified via a high-throughput screen in 2002. It is effective against all orthopoxviruses, including vaccinia, cowpox, ectromelia, rabbitpox, monkeypox, and Variola (smallpox) virus. Tecovirimat was approved by the FDA in July 2018 as the first drug ever approved to treat smallpox. Tecovirimat was later approved by Health Canada in December 2021, followed by the approval from the European Commission in January 2022. Other than smallpox, tecovirimat is also indicated to treat complications due to replication of the vaccinia virus following vaccination against smallpox, and to treat monkeypox and cowpox in adults and children. Tecovirimat is available as both oral and intravenous formulations.

Indications:

This drug is primarily indicated for: Tecovirimat is an inhibitor of the orthopoxvirus VP37 envelope wrapping protein and is indicated for the treatment of human smallpox disease in adults and pediatric patients weighing at least 3 kg. The efficacy of tecovirimat may be reduced in immunocompromised patients. In Europe, it is also indicated to treat complications due to replication of the vaccinia virus following vaccination against smallpox. In Europe, tecovirimat is also used to treat monkeypox and cowpox in adults and children. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Tecovirimat undergoes metabolic processing primarily in: Tecovirimat undergoes hydrolysis mediated by UGT1A1 and UGT1A4. Major metabolites are metabolites M4 (N-{3,5-dioxo-4-azatetracyclododec-11-en-4-yl}amine), M5 (3,5-dioxo-4-aminotetracyclododec-11-ene), and TFMBA (4 (trifluoromethyl) benzoic acid). None of the metabolites is pharmacologically active. None of the glucuronide conjugates was found as a major metabolite in plasma. The exact chemical structures of tecovirimat metabolites have not been fully characterized. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Tecovirimat are crucial for its therapeutic efficacy: Tecovirimat is readily absorbed following oral administration. Following oral administration of 600 mg tecovirimat in healthy adults, the mean steady-state AUC_0-24hr was 29816 hr x ng/mL and the C_max was 2159 ng/mL. Following intravenous administration of 200 mg tecovirimat every 12 hours, the mean steady-state AUC_0-24hr was 39405 hr x ng/mL and the C_max was 2630 ng/mL. The T_max is about six hours. The steady-state is achieved within four to six days. The oral bioavailability of tecovirimat is increased when taken with food. A moderate fat and calories meal increased the drug exposure (AUC) by 39% when tecovirimat was orally administered in conjunction with food. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Tecovirimat is an important consideration for its dosing schedule: The elimination half-life (CV%) was 21 (45%) hours following intravenous administration of 200 mg tecovirimat and 19 (29%) hours following oral administration of 600 mg tecovirimat. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Tecovirimat exhibits a strong affinity for binding with plasma proteins: Tecovirimat is 77-82% bound to human plasma proteins. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Tecovirimat from the body primarily occurs through: The major routes of elimination are through metabolism and renal elimination. Following oral administration, about 73% of the dose was excreted in urine, predominantly in the form of glucuronidated metabolites. About 23% of the dose was recovered in feces, predominantly as the unchanged parent drug. In urine, primary tecovirimat glucuronide conjugate and M4 glucuronide conjugate were the most abundant components accounting for means of 24.4% and 30.3% of dose, respectively. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Tecovirimat is distributed throughout the body with a volume of distribution of: The volume of distribution was 383 L following intravenous administration of 200 mg tecovirimat and 1030 L following oral administration of 600 mg tecovirimat. The blood-to-plasma ratio ranges from 0.62 to 0.90. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Tecovirimat is a critical factor in determining its safe and effective dosage: The clearance rate was 13 L/h following intravenous administration of 200 mg tecovirimat and 31 L/h following oral administration of 600 mg tecovirimat. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Tecovirimat exerts its therapeutic effects through: Tecovirimat is an antiviral drug that helps to prevent the spread of virus and reduce viremia. It is effective against all orthopoxviruses tested _in vitro_, including variola or smallpox virus. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Tecovirimat functions by: Successful viral replication leads to the formation of a number of infectious virion forms. Mature viruses are infectious but remain intracellularly until cell lysis. On the other hand, enveloped virion form is created when mature viruses wrap with late endosomal membranes. The formation of a wrapping complex for enveloped virions is mediated by the orthopoxvirus P37 protein. These egress-competent enveloped virions are released in a nonlytic fashion from the cell and play an essential role in cell-to-cell and long-range dissemination of the virus in the host. The P37 protein is encoded by a highly conserved gene in all members of the orthopoxvirus genus. P37 interacts with the Rab9 GTPase and TIP47, which are components of late endosome-derived transport vesicles. Interaction of P37 and Rab9 GTPase and TIP47 leads to the formation of the virus-specific wrapping complex for enveloped virions. Tecovirimat is an inhibitor of P37: it blocks the interaction of P37 with Rab9 and TIP47, preventing the formation of the wrapping complex. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Tecovirimat belongs to the class of organic compounds known as isoindolones. These are aromatic polycyclic compounds that an isoindole bearing a ketone, classified under the direct parent group Isoindolones. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Isoindoles and derivatives class, specifically within the Isoindolines subclass.

Categories:

Tecovirimat is categorized under the following therapeutic classes: Acids, Carbocyclic, Amides, Antiinfectives for Systemic Use, Antiviral Agents, Antivirals for Systemic Use, BCRP/ABCG2 Inhibitors, Benzene Derivatives, Benzoates, Cytochrome P-450 CYP2B6 Inducers, Cytochrome P-450 CYP2B6 Inducers (strength unknown), Cytochrome P-450 CYP2C19 Inhibitors, Cytochrome P-450 CYP2C19 Inhibitors (weak), Cytochrome P-450 CYP2C8 Inducers, Cytochrome P-450 CYP2C8 Inducers (weak), Cytochrome P-450 CYP2C8 Inhibitors, Cytochrome P-450 CYP3A Inducers, Cytochrome P-450 CYP3A4 Inducers, Cytochrome P-450 CYP3A4 Inducers (weak), Cytochrome P-450 Enzyme Inducers, Cytochrome P-450 Enzyme Inhibitors, Direct Acting Antivirals, Heterocyclic Compounds, Fused-Ring, Orthopoxvirus VP37 Envelope Wrapping Protein Inhibitor, UGT1A1 Substrates, UGT1A3 substrates, UGT1A4 substrates. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Tecovirimat include:

• Water Solubility:<1 mg/mL
• Melting Point: 196