Peringatan Keamanan

Alvespimycin exhibits a dose-limiting toxicity where most toxic effects were experienced at ? 80mg/m^2 in Phase I clinical trials. Common adverse effects include nausea, vomiting, fatigue, hematologic toxicity, liver enzyme disturbances and ocular disturbances including blurred vision and keratitis. They are reported to be generally reversible. The doses lower than 80mg/m^2 are well-tolerated. The dose-limiting

Alvespimycin

DB12442

small molecule investigational

Deskripsi

Alvespimycin is a derivative of geldanamycin and heat shock protein (HSP) 90 inhibitor. It has been used in trials studying the treatment of solid tumor in various cancer as an antitumor agent. In comparison to the first HSP90 inhibitor tanespimycin, it exhibits some pharmacologically desirable properties such as reduced metabolic liability, lower plasma protein binding, increased water solubility, higher oral bioavailability, reduced hepatotoxicity and superior antitumor activity ^A19243.

Struktur Molekul 2D

Berat 616.7455

Wujud solid

Peta Jejaring Molekuler

Obat Target Gen Interaksi Enzim Transporter Carrier

Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

1. Pendahuluan & Konsep

Fitur visualisasi ini dikembangkan menggunakan pendekatan Graph Theory untuk memetakan hubungan polifarmasi dan molekuler. Entitas (Obat, Target, Gen) direpresentasikan sebagai Simpul (Nodes), sedangkan hubungan biologisnya sebagai Sisi (Edges).

2. Sumber Data (Validasi)

Data Obat: Diekstraksi dari elemen drugbank-id dan name pada skema XML DrugBank.
Target Protein: Diambil dari elemen targets/target yang memuat polipeptida sasaran.
Genetik: Disinkronisasi dari sub-elemen gene-name dan varian snp-effects.
Genetik: Jumlah titik node dibatasi pada maksimal 10 (Slice=10) interaksi untuk menghindari tumpukan data.

3. Algoritma Visualisasi

Tata letak grafik menggunakan algoritma Force-Directed Graph (Barnes-Hut). Model fisika ini menerapkan gaya tolak-menolak antar simpul (Gravitasi: -3000) agar tidak tumpang tindih, serta gaya pegas (Spring: 0.04) pada garis penghubung untuk fleksibilitas interaksi.

4. Legenda Visual

Obat Utama (Pusat Analisis)

Target Protein (Mekanisme)

Gen (Faktor Genetik)

Metode ini mendukung analisis Precision Medicine dan evaluasi risiko Drug-Drug Interaction (DDI).

Profil Farmakokinetik

Waktu Paruh (Half-Life) The half-life across all dose levels ranged from 9.9 to 54.1 h (median, 18.2 h) [A19251].

Volume Distribusi At the maximum tolerated dose of 80mg/m^2, the mean Vd value is 385 L.

Klirens (Clearance) The mean clearance is 18.9 L/hr at the dose of 80mg/m^2.

Absorpsi

Increasing concentration of the drug results in dose-proportional increase in the plasma concentration. At the maximum tolerated dose of 80mg/m^2, the plasma concentration exceeded 63nM (mean IC50 for 17-DMAG in the NCI 60 human tumor cell line panel) for less than 24 hours in all patients. The mean peak concentration (Cmax) reached 2680 nmol/L at this dose.

Metabolisme

Alvespimycin demonstrates redox cycling catalyzed by purified human cytochrome P450 reductase (CYP3A4/3A5) to quinones and hydroquinones. It could also form glutathione conjugates at the 19-position on the quinone ring ^A19252. However in vivo and in vitro studies suggest that weak metabolism of alvespimysin occurs in humans.

Rute Eliminasi

Mainly renal and biliary elimination pathways. In a mice study, the excreted urine 24 hours post-dose recovered 10.6–14.8% of delivered dose unchanged ^A19244.

Interaksi Obat

0 Data

Tidak ada data.

Target Protein

Heat shock protein HSP 90-alpha HSP90AA1

Referensi & Sumber

Artikel (PubMed)

PMID: 21278242
Pacey S, Wilson RH, Walton M, Eatock MM, Hardcastle A, Zetterlund A, Arkenau HT, Moreno-Farre J, Banerji U, Roels B, Peachey H, Aherne W, de Bono JS, Raynaud F, Workman P, Judson I: A phase I study of the heat shock protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced solid tumors. Clin Cancer Res. 2011 Mar 15;17(6):1561-70. doi: 10.1158/1078-0432.CCR-10-1927. Epub 2011 Jan 28.
PMID: 24471734
Hu ZY, Lu J, Zhao Y: A physiologically based pharmacokinetic model of alvespimycin in mice and extrapolation to rats and humans. Br J Pharmacol. 2014 Jun;171(11):2778-89. doi: 10.1111/bph.12609.
PMID: 25920748
Hu Y, Bobb D, He J, Hill DA, Dome JS: The HSP90 inhibitor alvespimycin enhances the potency of telomerase inhibition by imetelstat in human osteosarcoma. Cancer Biol Ther. 2015;16(6):949-57. doi: 10.1080/15384047.2015.1040964. Epub 2015 Apr 28.
PMID: 23293352
Bae J, Munshi A, Li C, Samur M, Prabhala R, Mitsiades C, Anderson KC, Munshi NC: Heat shock protein 90 is critical for regulation of phenotype and functional activity of human T lymphocytes and NK cells. J Immunol. 2013 Feb 1;190(3):1360-71. doi: 10.4049/jimmunol.1200593. Epub 2013 Jan 4.
PMID: 19945858
Kummar S, Gutierrez ME, Gardner ER, Chen X, Figg WD, Zajac-Kaye M, Chen M, Steinberg SM, Muir CA, Yancey MA, Horneffer YR, Juwara L, Melillo G, Ivy SP, Merino M, Neckers L, Steeg PS, Conley BA, Giaccone G, Doroshow JH, Murgo AJ: Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies. Eur J Cancer. 2010 Jan;46(2):340-7. doi: 10.1016/j.ejca.2009.10.026. Epub 2009 Nov 27.
PMID: 18635747
Guo W, Reigan P, Siegel D, Ross D: Enzymatic reduction and glutathione conjugation of benzoquinone ansamycin heat shock protein 90 inhibitors: relevance for toxicity and mechanism of action. Drug Metab Dispos. 2008 Oct;36(10):2050-7. doi: 10.1124/dmd.108.022004. Epub 2008 Jul 17.

Contoh Produk & Brand

Produk: 0 • International brands: 0

Belum ada data produk/brand untuk obat ini pada database. Jalankan import DrugBank untuk mengisi field produk/brand.

Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.