Tapinarof
Identification
- Summary
Tapinarof is a therapeutic aryl hydrocarbon receptor-modulating agent (TAMA) indicated for the treatment of adult psoriasis.
- Brand Names
- Vtama
- Generic Name
- Tapinarof
- DrugBank Accession Number
- DB06083
- Background
Tapinarof is a novel, first-in-class, small-molecule AhR agonist that is indicated for the treatment of adult psoriasis. It is available as a topical cream to be applied to the affected area once daily.11,7 Tapiranof was first discovered as a metabolite (3,5-dihydroxy-4-isopropylstilbene) produced in Photorhabdus luminescens, a gram-negative bacillus that lives symbiotically with the Heterorhabditis nematodes.7 In 1959, it was noticed that Heterorhabditis with a high amount of 3,5-dihydroxy-4-isopropylstilbene did not putrefy once dead, thus suggesting its potential anti-inflammatory activity.7
Tapinarof received initial approval from the FDA in 2022.11
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 254.329
Monoisotopic: 254.13067982 - Chemical Formula
- C17H18O2
- Synonyms
- 3,5-Dihydroxy-4-isopropyl-trans-stilbene
- Benvitimod
- Tapinarof
- External IDs
- GSK-2894512
- GSK2894512
- WBI 1001
- WBI-1001
Pharmacology
- Indication
Tapinarof is indicated for the topical treatment of plaque psoriasis in adults.11
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Management of Psoriasis vulgaris (plaque psoriasis) •••••••••••• ••••• ••••• - Contraindications & Blackbox Warnings
- Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API
- Pharmacodynamics
The pharmacodynamics of tapinarof are unknown.11
- Mechanism of action
Tapinarof is a therapeutic aryl hydrocarbon receptor-modulating agent (TAMA) that binds to and activates the aryl hydrocarbon receptor (AhR). AhR is a ligand-dependent transcription factor that regulates gene expression in a variety of cell types, including macrophages, T-cells, antigen-presenting cells, fibroblasts, and keratinocytes.7 Upon binding to its ligand, AhR heterodimerizes with AhR nuclear translocator (ARNT) to form a complex with a high affinity for DNA binding.7,4 The AhR-ligand/ARNT complex can then bind to the specific DNA recognition sites to transcribe AhR-responsive genes.7,4 Additionally, AhR also exerts its effect through other transcription factors such as the nuclear factor κB and nuclear factor erythroid 2-related factor 2 (Nrf2), a downstream product of AhR-induced transcription that has antioxidant properties.8,7
Dysregulation of AhR is one of the hallmarks of psoriasis, as psoriasis patients have a higher serum concentration of AhR compared to healthy individuals.6 Treatment of AhR ligands in vitro also results in a gene expression profile that is implicated in the pathogenesis of psoriasis.6,4 For instance, AhR activation causes the expansion and differentiation of Th17 and Th22, two major T cells responsible for releasing inflammatory cytokines IL-17 and IL-22.9,6,4. Additionally, AhR activation also recruits persistent skin resident memory T cells, thus contributing to the chronicity of psoriasis.10 However, the specific binding of tapinarof to AhR modulates a unique set of genes that are dysregulated in psoriasis, distinctive from other AhR ligands.4,7 Further, tapinarof also induces barrier protein expression, such as filaggrin, hornerin, and involucrin, to restore the skin barrier and epidermal function and decrease oxidative stress.7,6,10 It is currently unknown why AhR ligands like tapinarof can reduce psoriatic inflammations in one setting but upregulate inflammatory genes in another setting.4
It is possible that the anti-inflammatory effect of tapinarof as an AhR agonist might be due to Nrf2.4 Although Nrf2 is a known downstream effector of AhR, not all AhR agonists activate this pathway. For instance, 2,3,7,8-tetrachlorodibenzo-p-dioxin, an AhR agonist, does not show any antioxidant activity after AhR activation.5 Therefore, it is hypothesized that the dual AhR/Nrf2 action of tapinarof is essential to the effect of tapinarof in treating psoriasis.6
Target Actions Organism AAryl hydrocarbon receptor agonistHumans - Absorption
No accumulation was observed with repeat topical application. Plasma concentration of tapinarof was below the quantifiable limits (BQL) of the assay (lower limit of quantification was 50 pg/mL) in 68% of the pharmacokinetic samples. On Day 1, mean ± SD values of Cmax and AUC0-last were 0.90 ± 1.4 ng/mL and 4.1 ± 6.3 ng.h/mL, respectively, following a mean daily dose of 5.23 g applied to a mean body surface area involvement of 27.2% (range 21 to 46%) in 21 subjects with moderate to severe plaque psoriasis. On Day 29, the mean ± SD Cmax and AUC0-last were 0.12 ± 0.15 ng/mL and 0.61 ± 0.65 ng.h/mL, respectively.11
- Volume of distribution
The Vss of tapinarof is estimated to be from 1270 to 1500 mL/kg.3
- Protein binding
Human plasma protein binding of tapinarof is approximately 99% in vitro.11
- Metabolism
Tapinarof is metabolized in the liver by multiple pathways including oxidation, glucuronidation, and sulfation in vitro.11CYP1A2 and CYP3A4 appears to be the major enzyme involved in the hepatic metabolism of tapinarof, while CYP2C9, CYP2C19, and CYP2D6 play a minor role.3
- Route of elimination
Not Available
- Half-life
Due to the insufficient data about the elimination phase, the terminal half-life of tapinarof cannot be determined.3
- Clearance
Not Available
- Adverse Effects
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- Toxicity
Long-term carcinogenicity studies were conducted in mice (daily topical administration at doses of 0.5, 1.5, and 3% tapinarof cream) and in rats (subcutaneous administration at doses of 0.1, 0.3, and 1 mg/kg/day tapinarof). No drug-related neoplasms were noted in mice after 98 (females) to 102 (males) weeks of daily topical administration at doses up to 3% tapinarof cream (44 times the MRHD based on AUC comparisons). No drug-related neoplasms were noted in female rats after 83 weeks of daily subcutaneous administration at up to 1 mg/kg/day tapinarof (9 times the MRHD based on AUC comparisons).11
Tapinarof revealed no evidence of mutagenicity or clastogenicity in an Ames assay, an in vitro mammalian chromosomal aberration assay, an in vitro mouse lymphoma assay, and two in vivo micronucleus assays in mice and rats.11
Tapinarof did not impair female fertility at subcutaneous doses up to 30 mg/kg/day (268 times the MRHD based on AUC comparisons).11
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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.Not Available
- Food Interactions
- No interactions found.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Vtama Cream 10 mg/1000mg Topical Dermavant Sciences, Inc. 2022-05-26 Not applicable US
Categories
- Drug Categories
- Aryl Hydrocarbon Receptor Agonist
- Benzene Derivatives
- Benzylidene Compounds
- Cytochrome P-450 CYP1A2 Substrates
- Cytochrome P-450 CYP2C19 Substrates
- Cytochrome P-450 CYP2C9 Substrates
- Cytochrome P-450 CYP2D6 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- Phenols
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as stilbenes. These are organic compounds containing a 1,2-diphenylethylene moiety. Stilbenes (C6-C2-C6 ) are derived from the common phenylpropene (C6-C3) skeleton building block. The introduction of one or more hydroxyl groups to a phenyl ring lead to stilbenoids.
- Kingdom
- Organic compounds
- Super Class
- Phenylpropanoids and polyketides
- Class
- Stilbenes
- Sub Class
- Not Available
- Direct Parent
- Stilbenes
- Alternative Parents
- Monocyclic monoterpenoids / Aromatic monoterpenoids / Phenylpropanes / Cumenes / Styrenes / Resorcinols / 1-hydroxy-4-unsubstituted benzenoids / 1-hydroxy-2-unsubstituted benzenoids / Organooxygen compounds / Hydrocarbon derivatives
- Substituents
- 1-hydroxy-2-unsubstituted benzenoid / 1-hydroxy-4-unsubstituted benzenoid / Aromatic homomonocyclic compound / Aromatic monoterpenoid / Benzenoid / Cumene / Hydrocarbon derivative / Monocyclic benzene moiety / Monocyclic monoterpenoid / Monoterpenoid
- Molecular Framework
- Aromatic homomonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 84HW7D0V04
- CAS number
- 79338-84-4
- InChI Key
- ZISJNXNHJRQYJO-CMDGGOBGSA-N
- InChI
- InChI=1S/C17H18O2/c1-12(2)17-15(18)10-14(11-16(17)19)9-8-13-6-4-3-5-7-13/h3-12,18-19H,1-2H3/b9-8+
- IUPAC Name
- 5-[(E)-2-phenylethenyl]-2-(propan-2-yl)benzene-1,3-diol
- SMILES
- CC(C)C1=C(O)C=C(\C=C\C2=CC=CC=C2)C=C1O
References
- General References
- Joyce SA, Brachmann AO, Glazer I, Lango L, Schwar G, Clarke DJ, Bode HB: Bacterial biosynthesis of a multipotent stilbene. Angew Chem Int Ed Engl. 2008;47(10):1942-5. doi: 10.1002/anie.200705148. [Article]
- Hu K, Webster JM: Antibiotic production in relation to bacterial growth and nematode development in Photorhabdus--Heterorhabditis infected Galleria mellonella larvae. FEMS Microbiol Lett. 2000 Aug 15;189(2):219-23. [Article]
- Bissonnette R, Vasist LS, Bullman JN, Collingwood T, Chen G, Maeda-Chubachi T: Systemic Pharmacokinetics, Safety, and Preliminary Efficacy of Topical AhR Agonist Tapinarof: Results of a Phase 1 Study. Clin Pharmacol Drug Dev. 2018 Jun;7(5):524-531. doi: 10.1002/cpdd.439. Epub 2018 Feb 1. [Article]
- Furue M, Hashimoto-Hachiya A, Tsuji G: Aryl Hydrocarbon Receptor in Atopic Dermatitis and Psoriasis. Int J Mol Sci. 2019 Oct 31;20(21). pii: ijms20215424. doi: 10.3390/ijms20215424. [Article]
- Kennedy LH, Sutter CH, Leon Carrion S, Tran QT, Bodreddigari S, Kensicki E, Mohney RP, Sutter TR: 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated production of reactive oxygen species is an essential step in the mechanism of action to accelerate human keratinocyte differentiation. Toxicol Sci. 2013 Mar;132(1):235-49. doi: 10.1093/toxsci/kfs325. Epub 2012 Nov 14. [Article]
- Smith SH, Jayawickreme C, Rickard DJ, Nicodeme E, Bui T, Simmons C, Coquery CM, Neil J, Pryor WM, Mayhew D, Rajpal DK, Creech K, Furst S, Lee J, Wu D, Rastinejad F, Willson TM, Viviani F, Morris DC, Moore JT, Cote-Sierra J: Tapinarof Is a Natural AhR Agonist that Resolves Skin Inflammation in Mice and Humans. J Invest Dermatol. 2017 Oct;137(10):2110-2119. doi: 10.1016/j.jid.2017.05.004. Epub 2017 Jun 6. [Article]
- Bissonnette R, Stein Gold L, Rubenstein DS, Tallman AM, Armstrong A: Tapinarof in the treatment of psoriasis: A review of the unique mechanism of action of a novel therapeutic aryl hydrocarbon receptor-modulating agent. J Am Acad Dermatol. 2021 Apr;84(4):1059-1067. doi: 10.1016/j.jaad.2020.10.085. Epub 2020 Nov 3. [Article]
- Nakahara T, Mitoma C, Hashimoto-Hachiya A, Takahara M, Tsuji G, Uchi H, Yan X, Hachisuka J, Chiba T, Esaki H, Kido-Nakahara M, Furue M: Antioxidant Opuntia ficus-indica Extract Activates AHR-NRF2 Signaling and Upregulates Filaggrin and Loricrin Expression in Human Keratinocytes. J Med Food. 2015 Oct;18(10):1143-9. doi: 10.1089/jmf.2014.3396. Epub 2015 May 18. [Article]
- Korn T, Bettelli E, Oukka M, Kuchroo VK: IL-17 and Th17 Cells. Annu Rev Immunol. 2009;27:485-517. doi: 10.1146/annurev.immunol.021908.132710. [Article]
- Fernandez-Gallego N, Sanchez-Madrid F, Cibrian D: Role of AHR Ligands in Skin Homeostasis and Cutaneous Inflammation. Cells. 2021 Nov 15;10(11). pii: cells10113176. doi: 10.3390/cells10113176. [Article]
- FDA Approved Drug Proucts: VTAMA (tapinarof) cream, for topical use [Link]
- External Links
- ChemSpider
- 4943924
- 2602286
- ChEMBL
- CHEMBL259571
- ZINC
- ZINC000005761533
- Wikipedia
- Tapinarof
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 Treatment Psoriasis 3 4 Recruiting Treatment Psoriasis 1 3 Completed Treatment Atopic Dermatitis 2 3 Completed Treatment Psoriasis Vulgaris (Plaque Psoriasis) 3 3 Recruiting Treatment Atopic Dermatitis 2
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Cream Topical 10 mg/1000mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US10426743 No 2019-10-01 2036-05-19 US US10195160 No 2019-02-05 2036-05-19 US US10647649 No 2020-05-12 2038-11-13 US US11458108 No 2016-05-19 2036-05-19 US US11597692 No 2018-11-13 2038-11-13 US US11590088 No 2019-11-13 2039-11-13 US US11612573 No 2016-05-19 2036-05-19 US US11617724 No 2016-05-19 2036-05-19 US US11622945 No 2016-05-19 2036-05-19 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0339 mg/mL ALOGPS logP 4.25 ALOGPS logP 4.95 Chemaxon logS -3.9 ALOGPS pKa (Strongest Acidic) 9.19 Chemaxon pKa (Strongest Basic) -5.9 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 2 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 40.46 Å2 Chemaxon Rotatable Bond Count 3 Chemaxon Refractivity 79.67 m3·mol-1 Chemaxon Polarizability 29.58 Å3 Chemaxon Number of Rings 2 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 splash10-0f7c-2390000000-592f88b3e3063bc46373 Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0a4i-0090000000-240b846e70eb7ac6bdaf Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0udi-0090000000-8c0b5fef049bcb2db1a5 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0udr-0090000000-a452e4c8fde64dc5319d Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-052k-0490000000-e68f71b73291ef999683 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0a4i-1970000000-347fc9c696dedb30e470 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-004i-0930000000-d721eae6c80848e4a8f8 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]- 179.0776187 predictedDarkChem Lite v0.1.0 [M-H]- 161.2049 predictedDeepCCS 1.0 (2019) [M+H]+ 182.2976187 predictedDarkChem Lite v0.1.0 [M+H]+ 163.5629 predictedDeepCCS 1.0 (2019) [M+Na]+ 180.2896187 predictedDarkChem Lite v0.1.0 [M+Na]+ 169.65605 predictedDeepCCS 1.0 (2019)
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Agonist
- General Function
- Transcription regulatory region dna binding
- Specific Function
- Ligand-activated transcriptional activator. Binds to the XRE promoter region of genes it activates. Activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes...
- Gene Name
- AHR
- Uniprot ID
- P35869
- Uniprot Name
- Aryl hydrocarbon receptor
- Molecular Weight
- 96146.705 Da
References
- FDA Approved Drug Proucts: VTAMA (tapinarof) cream, for topical use [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
- 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
- CYP1A2
- Uniprot ID
- P05177
- Uniprot Name
- Cytochrome P450 1A2
- Molecular Weight
- 58293.76 Da
References
- Bissonnette R, Vasist LS, Bullman JN, Collingwood T, Chen G, Maeda-Chubachi T: Systemic Pharmacokinetics, Safety, and Preliminary Efficacy of Topical AhR Agonist Tapinarof: Results of a Phase 1 Study. Clin Pharmacol Drug Dev. 2018 Jun;7(5):524-531. doi: 10.1002/cpdd.439. Epub 2018 Feb 1. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- 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
- Bissonnette R, Vasist LS, Bullman JN, Collingwood T, Chen G, Maeda-Chubachi T: Systemic Pharmacokinetics, Safety, and Preliminary Efficacy of Topical AhR Agonist Tapinarof: Results of a Phase 1 Study. Clin Pharmacol Drug Dev. 2018 Jun;7(5):524-531. doi: 10.1002/cpdd.439. Epub 2018 Feb 1. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- 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
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- Bissonnette R, Vasist LS, Bullman JN, Collingwood T, Chen G, Maeda-Chubachi T: Systemic Pharmacokinetics, Safety, and Preliminary Efficacy of Topical AhR Agonist Tapinarof: Results of a Phase 1 Study. Clin Pharmacol Drug Dev. 2018 Jun;7(5):524-531. doi: 10.1002/cpdd.439. Epub 2018 Feb 1. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- 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
- Bissonnette R, Vasist LS, Bullman JN, Collingwood T, Chen G, Maeda-Chubachi T: Systemic Pharmacokinetics, Safety, and Preliminary Efficacy of Topical AhR Agonist Tapinarof: Results of a Phase 1 Study. Clin Pharmacol Drug Dev. 2018 Jun;7(5):524-531. doi: 10.1002/cpdd.439. Epub 2018 Feb 1. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
- Gene Name
- CYP2D6
- Uniprot ID
- P10635
- Uniprot Name
- Cytochrome P450 2D6
- Molecular Weight
- 55768.94 Da
References
- Bissonnette R, Vasist LS, Bullman JN, Collingwood T, Chen G, Maeda-Chubachi T: Systemic Pharmacokinetics, Safety, and Preliminary Efficacy of Topical AhR Agonist Tapinarof: Results of a Phase 1 Study. Clin Pharmacol Drug Dev. 2018 Jun;7(5):524-531. doi: 10.1002/cpdd.439. Epub 2018 Feb 1. [Article]
Drug created at November 18, 2007 18:29 / Updated at March 22, 2023 02:02