Peringatan Keamanan

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).L41845

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.L41845

Tapinarof did not impair female fertility at subcutaneous doses up to 30 mg/kg/day (268 times the MRHD based on AUC comparisons).L41845

Tapinarof

DB06083

small molecule approved investigational

Deskripsi

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.L41845, A248790 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.A248790 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.A248790

Tapinarof received initial approval from the FDA in 2022.L41845

Struktur Molekul 2D

Berat 254.329
Wujud solid

Peta Jejaring Molekuler
Legenda: ObatTargetGenEnzim(Panah → menunjukkan arah efek / relasi)TransporterCarrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) Due to the insufficient data about the elimination phase, the terminal half-life of tapinarof cannot be determined.[A248725]
Volume Distribusi The Vss of tapinarof is estimated to be from 1270 to 1500 mL/kg.[A248725]
Klirens (Clearance) -

Absorpsi

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.L41845

Metabolisme

Tapinarof is metabolized in the liver by multiple pathways including oxidation, glucuronidation, and sulfation in vitro.L41845CYP1A2 and CYP3A4 appears to be the major enzyme involved in the hepatic metabolism of tapinarof, while CYP2C9, CYP2C19, and CYP2D6 play a minor role.A248725

Rute Eliminasi

Data eliminasi belum tersedia.

Interaksi Obat

0 Data
Tidak ada data.

Target Protein

Aryl hydrocarbon receptor AHR

Referensi & Sumber

Artikel (PubMed)
  • PMID: 18236486
    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.
  • PMID: 10930742
    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.
  • PMID: 29389078
    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.
  • PMID: 31683543
    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.
  • PMID: 23152189
    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.
  • PMID: 28595996
    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.
  • PMID: 33157177
    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.
  • PMID: 26061570
    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.
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Contoh Produk & Brand

Produk: 1 • International brands: 0
Produk
  • Vtama
    Cream • 10 mg/1000mg • Topical • US • Approved

Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.
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