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
Weight
Average: 376.335
Monoisotopic: 376.10347684
Chemical Formula
C19H15F3N2O3
Synonyms
  • ST-246
  • Tecovirimat
External IDs
  • SIGA-246
  • ST 246
  • ST-246

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
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

TargetActionsOrganism
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 AUC0-24hr was 29816 hr x ng/mL and the Cmax was 2159 ng/mL. Following intravenous administration of 200 mg tecovirimat every 12 hours, the mean steady-state AUC0-24hr was 39405 hr x ng/mL and the Cmax was 2630 ng/mL. The Tmax 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
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
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.
DrugInteraction
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Tecovirimat.
Anthrax vaccineThe therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Tecovirimat.
Bacillus calmette-guerin substrain connaught live antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain connaught live antigen can be decreased when used in combination with Tecovirimat.
Bacillus calmette-guerin substrain russian BCG-I live antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain russian BCG-I live antigen can be decreased when used in combination with Tecovirimat.
Bacillus calmette-guerin substrain tice live antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain tice live antigen can be decreased when used in combination with Tecovirimat.
BCG vaccineThe therapeutic efficacy of BCG vaccine can be decreased when used in combination with Tecovirimat.
Human adenovirus e serotype 4 strain cl-68578 antigenThe therapeutic efficacy of Human adenovirus e serotype 4 strain cl-68578 antigen can be decreased when used in combination with Tecovirimat.
MidazolamThe serum concentration of Midazolam can be decreased when it is combined with Tecovirimat.
RepaglinideThe serum concentration of Repaglinide can be increased when it is combined with Tecovirimat.
Rubella virus vaccineThe therapeutic efficacy of Rubella virus vaccine can be decreased when used in combination with Tecovirimat.
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Food Interactions
  • Take with food. Take tecovirimat within 30 minutes of eating a fatty meal containing approximately 25 grams of fat.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Tecovirimat monohydrateSB96YO2BR81162664-19-8QRHXYGPOQKLBJP-NPIFKJBVSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Tecovirimat SigaCapsule200 mgOralSiga Technologies Netherlands B.V.2022-05-04Not applicableEU flag
TpoxxCapsule200 mg/1OralSIGA Technologies, Inc.2018-08-31Not applicableUS flag
TpoxxInjection, solution, concentrate10 mg/1mLIntravenousSIGA Technologies, Inc.2022-05-31Not applicableUS flag
TpoxxCapsule200 mgOralSIGA Technologies, Inc.2022-04-07Not applicableCanada flag

Categories

ATC Codes
J05AX24 — Tecovirimat
Drug Categories
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
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
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]
PubChem Compound
16124688
PubChem Substance
347828336
ChemSpider
17281586
ChEMBL
CHEMBL1257073
ZINC
ZINC000035323125
Wikipedia
Tecovirimat

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedOtherVariola Major (Smallpox)1
4Not Yet RecruitingOtherVariola Major (Smallpox)1
3CompletedTreatmentVariola Major (Smallpox)1
3RecruitingTreatmentVariola Major (Smallpox)1
2CompletedNot AvailableOrthopoxviral Disease1
2RecruitingTreatmentVariola Major (Smallpox)1
1CompletedTreatmentHealthy Subjects (HS)1
1CompletedTreatmentMonkeypox / Orthopoxviral Disease / Variola Major (Smallpox)1
1WithdrawnTreatmentVaccinia1
Not AvailableAvailableNot AvailableMonkeypox / Variola Major (Smallpox)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral200 mg/1
CapsuleOral200 mg
Injection, solution, concentrateIntravenous10 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7737168No2010-06-152027-05-03US flag
US8802714No2014-08-122024-06-18US flag
US8530509No2013-09-102024-06-18US flag
US9339466No2016-05-172031-03-23US flag
US8124643No2012-02-282024-06-18US flag
US8039504No2011-10-182027-07-23US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)196https://www.ema.europa.eu/en/documents/assessment-report/tecovirimat-siga-epar-public-assessment-report_en.pdf
water solubility<1 mg/mLhttps://www.selleck.cn/msds/MSDS_S3380.pdf
Predicted Properties
PropertyValueSource
Water Solubility0.021 mg/mLALOGPS
logP2.03ALOGPS
logP2.07ChemAxon
logS-4.2ALOGPS
pKa (Strongest Acidic)9.15ChemAxon
pKa (Strongest Basic)-6.2ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area66.48 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity89.45 m3·mol-1ChemAxon
Polarizability34.02 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

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insights and accelerate drug research.
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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]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
References
  1. FDA Approved Drug Products: TPOXX (tecovirimat) capsules for oral use [Link]
  2. Summary of Product Characteristics: Tecovirimat (tecovirimat) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A3
Uniprot ID
P35503
Uniprot Name
UDP-glucuronosyltransferase 1-3
Molecular Weight
60337.835 Da
References
  1. Summary of Product Characteristics: Tecovirimat (tecovirimat) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Protein homodimerization activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A4
Uniprot ID
P22310
Uniprot Name
UDP-glucuronosyltransferase 1-4
Molecular Weight
60024.535 Da
References
  1. FDA Approved Drug Products: TPOXX (tecovirimat) capsules for oral use [Link]
  2. Summary of Product Characteristics: Tecovirimat (tecovirimat) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inducer
Curator comments
Tecovirimat and its M4 metabolite are inducers of cytochrome P450 (CYP)3A.
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: TPOXX (tecovirimat) capsules, for oral use or injection, for intravenous use [Link]
  2. Summary of Product Characteristics: Tecovirimat (tecovirimat) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. FDA Approved Drug Products: TPOXX (tecovirimat) capsules, for oral use or injection, for intravenous use [Link]
  2. Summary of Product Characteristics: Tecovirimat (tecovirimat) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. FDA Approved Drug Products: TPOXX (tecovirimat) capsules, for oral use or injection, for intravenous use [Link]
  2. Summary of Product Characteristics: Tecovirimat (tecovirimat) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inducer
Curator comments
Tecovirimat and its M4 metabolite are inducers of cytochrome P450 (CYP)2B6.
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. Summary of Product Characteristics: Tecovirimat (tecovirimat) oral capsules [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Tecovirimat inhibited Breast Cancer Resistance Protein (BCRP) in vitro.
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. FDA Approved Drug Products: TPOXX (tecovirimat) capsules, for oral use or injection, for intravenous use [Link]

Drug created at October 20, 2016 21:11 / Updated at May 28, 2022 09:03