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Orthopoxvirus VP37 protein inhibitor23
Tecovirimat is an orally available small molecule inhibitor of the orthopoxvirus VP37 envelope wrapping protein indicated for the treatment of human smallpox disease in adults and children weighing ≥13 kg.52 It was granted orphan drug status in 2006.21 Tecovirimat is the first approval of a drug to treat smallpox and it is the first-in-class VP37 inhibitor. The effectiveness of tecovirimat (ST-246)129 was not determined in humans due to ethical constraints.23 Rather, tecovirimat was approved under FDA’s Animal Efficacy Rule on the basis of survival in 2 animal models of orthopoxvirus infections.129-133 The human safety of tecovirimat was established in clinical trials that enrolled healthy human volunteers.52,130,134
Tecovirimat was developed in collaboration with the U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority and other partners129,132 as a medical countermeasure against potential weaponization of the virus.23 Tecovirimat was identified as a candidate for development from the high-throughput screen of 356,240 compounds.129 It was selected for further development from among 759 compounds found to be capable of inhibiting the poxvirus cytopathic effect in cell cultures.129 Successful drug approval was accompanied by FDA’s first Material Threat Medical Countermeasure Priority Review voucher for the sponsor, SIGA Technologies.23,31,132,133
Although smallpox disease was declared eradicated in 1980, as long as official and clandestine sources of live variola virus still exist, disease resurgence remains a threat.129,132,135 Tecovirimat has been added to the U.S. Strategic National Stockpile in the event that smallpox disease reappears.23,132,133
Tecovirimat prevents the systemic spread of smallpox infection by inhibiting the activity of the orthopoxvirus VP37 protein, a protein that is encoded by and highly conserved in all members of the orthopoxvirus genus.52 Tecovirimat blocks interaction of the virus with cellular membrane trafficking proteins, which prevents extracellular forms of the virus from budding out from infected cells.67,135 Trapping smallpox particles in infected cells causes the infection to slow, and allows time for the human immune system to clear the infection. Predictably, the efficacy of tecovirimat may be reduced in patients who are immunocompromised.52 The possibility of reduced efficacy due to viral resistance to tecovirimat also has been suggested.130,136 Tecovirimat belongs to the class of organic compounds known as isoindolones137 (Figure P1-8). It is metabolized to inactive metabolites by hydrolysis of the amide bond and glucuronidation. It is a weak inhibitor of CYPs 2C8 and 2C19, a weak inducer of CYP3A4, a substrate of UGTs 1A1 and 1A4, and an inhibitor of breast cancer resistance protein (BCRP).52 It is excreted predominantly through the kidneys as glucuronidate metabolites, with ~23% eliminated in feces.137 The half-life is 20 hours.52 The recommended dose of tecovirimat for adults and children ≥40 kg is 600 mg twice daily for 14 days taken within 30 minutes after a full meal of moderate or high fat content.52 Simulation was used to arrive at pediatric dosing regimens that will approximate the systemic exposures observed in adults.52
The safety of tecovirimat was evaluated in 359 healthy adult subjects 18–79 years of age in a phase 3 clinical trial.52,130 Of these 359 subjects, 336 subjects received ≥23 of the 28 doses targeted for administration.52 No obvious safety signals were detected, and the drug appeared to have good tolerability. The most common side effects were headache, nausea, abdominal pain, and vomiting.52
Chemical structure of tecovirimat138 (PubChem CID: 16124688; IUPAC Name: N-[(1S,2S,6R,7R,8R,10S)-3,5-dioxo-4-azatetracyclo-dodec-11-en-4-yl]-4-(trifluoromethyl)benzamide).
Chapter 62. Antiviral Agents (Nonretroviral)
eChapter 2018: The Goodman & Gilman Year in Review New and Noteworthy FDA Approvals