Tecovirimat

Identification

Summary

Tecovirimat is an antiviral medication used to treat smallpox, monkeypox, and cowpox.

Brand Names

Tpoxx

Generic Name

Tecovirimat

DrugBank Accession Number

DB12020

Background

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.^2,5 Tecovirimat is an antiviral drug that was identified via a high-throughput screen in 2002.² It is effective against all orthopoxviruses, including vaccinia, cowpox, ectromelia, rabbitpox, monkeypox, and Variola (smallpox) virus.^1,4

Tecovirimat was approved by the FDA in July 2018 as the first drug ever approved to treat smallpox.^6,5 Tecovirimat was later approved by Health Canada in December 2021,⁷ followed by the approval from the European Commission in January 2022.⁹ 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.⁸ Tecovirimat is available as both oral and intravenous formulations.¹⁰

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Tecovirimat (DB12020)

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Weight

Average: 376.335
Monoisotopic: 376.10347684

Chemical Formula

C₁₉H₁₅F₃N₂O₃

Synonyms

• ST-246
• Tecovirimat

External IDs

• SIGA-246
• ST 246
• ST-246

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Pharmacology

Indication

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.¹⁰ In Europe, it is also indicated to treat complications due to replication of the vaccinia virus following vaccination against smallpox.⁸

In Europe, tecovirimat is also used to treat monkeypox and cowpox in adults and children.⁸

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Complication of smallpox vaccination		••••••••••••	••••••••••• •••••• •••••••••	•••• •••••• •• •• •• ••• ••••••• •••••••• ••••••••••••	•••••••
Treatment of	Cow pox		••••••••••••	••••••••••• •••••• •••••••••	•••• •••••• •• •• •• ••• ••••••	•••••••
Treatment of	Monkeypox		••••••••••••	••••••••••• •••••• •••••••••	•••• •••••• •• •• •• ••• ••••••	•••••••
Treatment of	Variola major (smallpox)		••••••••••••	••••••••••• •••••• •••••••••	•••• •••••• •• •• •• ••• ••••••	•••••••
Treatment of	Variola major (smallpox)		••••••••••••	••••••••••• •••••• •••••••••	•••••••• •• ••••• • ••	•••••••• •••••••••

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Contraindications & Blackbox Warnings

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Pharmacodynamics

Tecovirimat is an antiviral drug that helps to prevent the spread of virus ¹⁰ and reduce viremia.² It is effective against all orthopoxviruses tested in vitro, including variola or smallpox virus.¹

Mechanism of action

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.² These egress-competent enveloped virions are released in a nonlytic fashion from the cell ² and play an essential role in cell-to-cell and long-range dissemination of the virus in the host.^1,8

The P37 protein is encoded by a highly conserved gene in all members of the orthopoxvirus genus.¹⁰ 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.² Tecovirimat is an inhibitor of P37: it blocks the interaction of P37 with Rab9 and TIP47, preventing the formation of the wrapping complex.^1,2,8,10

Target	Actions	Organism
AEnvelope protein F13	inhibitor	Variola virus (isolate Human/India/Ind3/1967)

Absorption

Tecovirimat is readily absorbed following oral administration.² 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.¹⁰ The steady-state is achieved within four to six days.^3,10

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.⁸

Volume of distribution

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 0.90.¹⁰

Protein binding

Tecovirimat is 77-82% bound to human plasma proteins.¹⁰

Metabolism

Tecovirimat undergoes hydrolysis mediated by UGT1A1 and UGT1A4.¹⁰ Major metabolites are metabolites M4 (N-{3,5-dioxo-4-azatetracyclo[5.3.2.0{2,6}.0{8,10}]dodec-11-en-4-yl}amine), M5 (3,5-dioxo-4-aminotetracyclo[5.3.2.0{2,6}.0{8,10}]dodec-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.⁸ The exact chemical structures of tecovirimat metabolites have not been fully characterized.

Route of elimination

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.^10,8 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.⁸

Half-life

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.¹⁰

Clearance

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.¹⁰

Adverse Effects

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Toxicity

In single-dose toxicity studies, no LD50 has been reached even when tecovirimat was given at very high doses (2000 mg/kg) in mice or non-human primates.¹¹ There is no clinical experience with overdosage of tecovirimat. In case of overdosage, patients should be monitored for any signs or symptoms of adverse effects. Hemodialysis is not expected to effectively remove tecovirimat in overdosed patients.¹⁰

Pathways

Not Available

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Not Available

Interactions

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This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abemaciclib	The metabolism of Abemaciclib can be increased when combined with Tecovirimat.
Abrocitinib	The metabolism of Abrocitinib can be decreased when combined with Tecovirimat.
Acalabrutinib	The metabolism of Acalabrutinib can be increased when combined with Tecovirimat.
Acenocoumarol	The metabolism of Acenocoumarol can be increased when combined with Tecovirimat.
Adenovirus type 7 vaccine live	The therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Tecovirimat.

Food Interactions

• Take with food. Take tecovirimat within 30 minutes of eating a fatty meal containing approximately 25 grams of fat.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Tecovirimat monohydrate	SB96YO2BR8	1162664-19-8	QRHXYGPOQKLBJP-NPIFKJBVSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Tecovirimat Siga	Capsule	200 mg	Oral	Siga Technologies Netherlands B.V.	2022-05-04	Not applicable
Tpoxx	Capsule	200 mg	Oral	SIGA Technologies, Inc.	2022-04-07	Not applicable
Tpoxx	Capsule	200 mg/1	Oral	SIGA Technologies, Inc.	2018-08-31	Not applicable
Tpoxx	Injection, solution, concentrate	10 mg/1mL	Intravenous	SIGA Technologies, Inc.	2022-05-31	Not applicable

Categories

ATC Codes

J05AX24 — Tecovirimat

• J05AX — Other antivirals
• J05A — DIRECT ACTING ANTIVIRALS
• J05 — ANTIVIRALS FOR SYSTEMIC USE
• J — ANTIINFECTIVES FOR SYSTEMIC USE

Drug Categories

• Acids, Carbocyclic
• Amides
• Anti-Infective Agents
• 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
• Imides
• Isoindoles
• Orthopoxvirus VP37 Envelope Wrapping Protein Inhibitor
• Phthalic Acids
• UGT1A1 Substrates
• UGT1A3 substrates
• UGT1A4 substrates

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as isoindolones. These are aromatic polycyclic compounds that an isoindole bearing a ketone.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Isoindoles and derivatives

Sub Class

Isoindolines

Direct Parent

Isoindolones

Alternative Parents

Trifluoromethylbenzenes / Benzoic acids and derivatives / Benzoyl derivatives / Pyrrolidine-2-ones / Dicarboximides / Lactams / Carboxylic acid hydrazides / Azacyclic compounds / Organonitrogen compounds / Organofluorides / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds / Alkyl fluorides

show 4 more

Substituents

2-pyrrolidone / Alkyl fluoride / Alkyl halide / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Benzoic acid or derivatives / Benzoyl / Carbonyl group / Carboxylic acid derivative / Carboxylic acid hydrazide / Dicarboximide / Hydrocarbon derivative / Isoindolone / Lactam / Monocyclic benzene moiety / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organofluoride / Organohalogen compound / Organonitrogen compound / Organooxygen compound / Pyrrolidine / Pyrrolidone / Trifluoromethylbenzene

show 16 more

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

F925RR824R

CAS number

869572-92-9

InChI Key

CSKDFZIMJXRJGH-VWLPUNTISA-N

InChI

InChI=1S/C19H15F3N2O3/c20-19(21,22)9-3-1-8(2-4-9)16(25)23-24-17(26)14-10-5-6-11(13-7-12(10)13)15(14)18(24)27/h1-6,10-15H,7H2,(H,23,25)/t10-,11+,12+,13-,14-,15+

IUPAC Name

N-[(1R,2R,6S,7S,8S,10R)-3,5-dioxo-4-azatetracyclo[5.3.2.0^{2,6}.0^{8,10}]dodec-11-en-4-yl]-4-(trifluoromethyl)benzamide

SMILES

FC(F)(F)C1=CC=C(C=C1)C(=O)NN1C(=O)[C@H]2[C@H]([C@H]3C=C[C@@H]2[C@@H]2C[C@H]32)C1=O

References

General References

1. Grosenbach DW, Honeychurch K, Rose EA, Chinsangaram J, Frimm A, Maiti B, Lovejoy C, Meara I, Long P, Hruby DE: Oral Tecovirimat for the Treatment of Smallpox. N Engl J Med. 2018 Jul 5;379(1):44-53. doi: 10.1056/NEJMoa1705688. [Article]
2. Grosenbach DW, Jordan R, Hruby DE: Development of the small-molecule antiviral ST-246 as a smallpox therapeutic. Future Virol. 2011 May;6(5):653-671. doi: 10.2217/fvl.11.27. [Article]
3. Jordan R, Chinsangaram J, Bolken TC, Tyavanagimatt SR, Tien D, Jones KF, Frimm A, Corrado ML, Pickens M, Landis P, Clarke J, Marbury TC, Hruby DE: Safety and pharmacokinetics of the antiorthopoxvirus compound ST-246 following repeat oral dosing in healthy adult subjects. Antimicrob Agents Chemother. 2010 Jun;54(6):2560-6. doi: 10.1128/AAC.01689-09. Epub 2010 Apr 12. [Article]
4. Mucker EM, Goff AJ, Shamblin JD, Grosenbach DW, Damon IK, Mehal JM, Holman RC, Carroll D, Gallardo N, Olson VA, Clemmons CJ, Hudson P, Hruby DE: Efficacy of tecovirimat (ST-246) in nonhuman primates infected with variola virus (Smallpox). Antimicrob Agents Chemother. 2013 Dec;57(12):6246-53. doi: 10.1128/AAC.00977-13. Epub 2013 Oct 7. [Article]
5. FDA approves the first drug with an indication for treatment of smallpox [Link]
6. FDA approves first smallpox indicated treatment [Link]
7. BioSpace News: SIGA Announces Health Canada Regulatory Approval of Oral TPOXX® [Link]
8. Summary of Product Characteristics: Tecovirimat (tecovirimat) oral capsules [Link]
9. GlobeNewsWire News Release: SIGA Technologies Receives Approval from the European Medicines Agency for Tecovirimat [Link]
10. FDA Approved Drug Products: TPOXX (tecovirimat) capsules, for oral use or injection, for intravenous use [Link]
11. FDA ADVISORY COMMITTEE BRIEFING DOCUMENT: Tecovirimat for the Treatment of Smallpox Disease (May 1, 2018) [Link]

External Links

PubChem Compound

16124688

PubChem Substance

347828336

ChemSpider

17281586

ChEMBL

CHEMBL1257073

ZINC

ZINC000035323125

Wikipedia

Tecovirimat

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Completed	Other	Variola Major (Smallpox)	2
4	Not Yet Recruiting	Treatment	Monkeypox	1
3	Completed	Treatment	Variola Major (Smallpox)	2
3	Not Yet Recruiting	Treatment	Monkeypox	1
3	Recruiting	Treatment	Monkeypox / Mpox	2

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule	Oral	200 mg
Capsule	Oral	200 mg/1
Injection, solution, concentrate	Intravenous	10 mg/1mL

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US7737168	No	2010-06-15	2027-05-03
US8802714	No	2014-08-12	2024-06-18
US8530509	No	2013-09-10	2024-06-18
US9339466	No	2016-05-17	2031-03-23
US8124643	No	2012-02-28	2024-06-18
US8039504	No	2011-10-18	2027-07-23
US9907859	No	2018-03-06	2031-08-02
US9233097	No	2016-01-12	2031-08-02
US10576165	No	2020-03-03	2031-08-02

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	196	https://www.ema.europa.eu/en/documents/assessment-report/tecovirimat-siga-epar-public-assessment-report_en.pdf
water solubility	<1 mg/mL	https://www.selleck.cn/msds/MSDS_S3380.pdf

Predicted Properties

Property	Value	Source
Water Solubility	0.021 mg/mL	ALOGPS
logP	2.03	ALOGPS
logP	2.07	Chemaxon
logS	-4.2	ALOGPS
pKa (Strongest Acidic)	9.15	Chemaxon
pKa (Strongest Basic)	-6.2	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	3	Chemaxon
Hydrogen Donor Count	1	Chemaxon
Polar Surface Area	66.48 Å2	Chemaxon
Rotatable Bond Count	3	Chemaxon
Refractivity	89.45 m3·mol-1	Chemaxon
Polarizability	34.02 Å3	Chemaxon
Number of Rings	5	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	splash10-00xr-1902000000-33811607cbbf75d30d1c
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-004i-0009000000-dc9ca1d3fb76988bbfe5
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-004i-0009000000-d3df5227be55f614408a
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-004r-0209000000-4c3cf9bd3fdddacaface
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-004i-0409000000-9205e6b973185852af86
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-014r-1900000000-97205f6dd8015a6ba29c
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-00or-0897000000-d6feedd9e70279e61ff5
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	184.10957	predicted	DeepCCS 1.0 (2019)
[M+H]+	186.02293	predicted	DeepCCS 1.0 (2019)
[M+Na]+	191.98979	predicted	DeepCCS 1.0 (2019)

Targets

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Details1. Envelope protein F13

Kind

Protein

Organism

Variola virus (isolate Human/India/Ind3/1967)

Pharmacological action

Yes

Actions

Inhibitor

General Function

Envelope protein associated with the inner side of the enveloped virion (EV) membrane.

Specific Function

Catalytic activity

Gene Name

Not Available

Uniprot ID

P33815

Uniprot Name

Envelope protein F13

Molecular Weight

41902.245 Da

References

1. Duraffour S, Andrei G, Snoeck R: Tecovirimat, a p37 envelope protein inhibitor for the treatment of smallpox infection. IDrugs. 2010 Mar;13(3):181-91. [Article]
2. Mucker EM, Goff AJ, Shamblin JD, Grosenbach DW, Damon IK, Mehal JM, Holman RC, Carroll D, Gallardo N, Olson VA, Clemmons CJ, Hudson P, Hruby DE: Efficacy of tecovirimat (ST-246) in nonhuman primates infected with variola virus (Smallpox). Antimicrob Agents Chemother. 2013 Dec;57(12):6246-53. doi: 10.1128/AAC.00977-13. Epub 2013 Oct 7. [Article]
3. FDA Approved Drug Products: TPOXX (tecovirimat) capsules, for oral use or injection, for intravenous use [Link]

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Drug created at October 20, 2016 21:11 / Updated at September 02, 2022 17:58