Peringatan Keamanan

Data regarding overdoses of melphalan flufenamide are not readily available.L32173 However, nonclinical safety studies in dogs have shown an increased risk of mortality in subjects receiving higher than recommended doses.L32173 Patients should be treated with symptomatic and supportive measures.

Melphalan flufenamide

DB16627

small molecule approved withdrawn

Deskripsi

Melphalan flufenamide, also known as melflufen or J1, is a prodrug of melphalan.A230123,L32173 Melphalan flufenamide is more readily uptaken by cells than melphalan, and is cleaved to the active metabolite by aminopeptidases.A230123 In vitro models show that melphalan is 10 to hundreds of times more potent than melphalan.A230123 The increased potency makes melphalan flufenamide a treatment option for patients with relapsed or refractory multiple myeloma who have attempted at least 4 lines of therapy already.A230143,L32173

Melphalan flufenamide was granted FDA approval on 26 February 2021.L32173. It has since been withdrawn from the market in the wake of the phase 3 OCEAN trial which showed a decrease in overall survival in comparison to standard treatment with pomalidomide and dexamethasone despite superior progression-free survival.L39085, L39090

Struktur Molekul 2D

Berat 498.42
Wujud solid

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

Profil Farmakokinetik

Waktu Paruh (Half-Life) The mean elimination half life of melphalan flufenamide is 2.1 minutes and of melphalan is 70 minutes.[L32173]
Volume Distribusi The mean volume of distribution of melphalan flufenamide is 35 L and of melphalan is 76 L.[L32173]
Klirens (Clearance) The mean clearance of melphalan flufenamide is 692 L/h and of melphalan is 23 L/h.[L32173]

Absorpsi

For a 40 mg intravenous infusion, the active metabolite reaches a Cmax of 432 ng/mL, with a Tmax of 4-15 minutes, and an AUC of 3143 h\*µg/mL.A230123,L32173

Metabolisme

Melphalan flufenamide is metabolised to desethyl-melphalan and melphalan.L32173 Melphalan is spontaneously hydrolyzed to monohydroxy-melphalan and dihydroxy-melphalan.L32173

Rute Eliminasi

Data regarding the route of elimination of melphalan flufenamide are not readily available.L32173 Free melphalan undergoes rapid and spontaneous decomposition, complicating studies on the route of elimination.A230188 However, it is expected to be mainly renally excreted.A230188

Interaksi Obat

0 Data
Tidak ada data.

Target Protein

DNA

Referensi & Sumber

Artikel (PubMed)
  • PMID: 29029544
    Wickstrom M, Nygren P, Larsson R, Harmenberg J, Lindberg J, Sjoberg P, Jerling M, Lehmann F, Richardson P, Anderson K, Chauhan D, Gullbo J: Melflufen - a peptidase-potentiated alkylating agent in clinical trials. Oncotarget. 2017 Jun 8;8(39):66641-66655. doi: 10.18632/oncotarget.18420. eCollection 2017 Sep 12.
  • PMID: 32992506
    Mateos MV, Blade J, Bringhen S, Ocio EM, Efebera Y, Pour L, Gay F, Sonneveld P, Gullbo J, Richardson PG: Melflufen: A Peptide-Drug Conjugate for the Treatment of Multiple Myeloma. J Clin Med. 2020 Sep 27;9(10). pii: jcm9103120. doi: 10.3390/jcm9103120.
  • PMID: 27098276
    Ray A, Ravillah D, Das DS, Song Y, Nordstrom E, Gullbo J, Richardson PG, Chauhan D, Anderson KC: A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells. Br J Haematol. 2016 Aug;174(3):397-409. doi: 10.1111/bjh.14065. Epub 2016 Apr 20.
  • PMID: 7545551
    Osborne MR, Lawley PD, Crofton-Sleigh C, Warren W: Products from alkylation of DNA in cells by melphalan: human soft tissue sarcoma cell line RD and Escherichia coli WP2. Chem Biol Interact. 1995 Aug 18;97(3):287-96. doi: 10.1016/0009-2797(95)03623-t.
  • PMID: 7527485
    Povirk LF, Shuker DE: DNA damage and mutagenesis induced by nitrogen mustards. Mutat Res. 1994 Dec;318(3):205-26. doi: 10.1016/0165-1110(94)90015-9.
  • PMID: 8781575
    Lawley PD, Phillips DH: DNA adducts from chemotherapeutic agents. Mutat Res. 1996 Aug 17;355(1-2):13-40. doi: 10.1016/0027-5107(96)00020-6.
  • PMID: 20573084
    Nath CE, Shaw PJ, Trotman J, Zeng L, Duffull SB, Hegarty G, McLachlan AJ, Gurney H, Kerridge I, Kwan YL, Presgrave P, Tiley C, Joshua D, Earl J: Population pharmacokinetics of melphalan in patients with multiple myeloma undergoing high dose therapy. Br J Clin Pharmacol. 2010 May;69(5):484-97. doi: 10.1111/j.1365-2125.2010.03638.x.
  • PMID: 2910515
    Gera S, Musch E, Osterheld HK, Loos U: Relevance of the hydrolysis and protein binding of melphalan to the treatment of multiple myeloma. Cancer Chemother Pharmacol. 1989;23(2):76-80. doi: 10.1007/BF00273521.

Contoh Produk & Brand

Produk: 2 • International brands: 1
Produk
  • Pepaxti
    Injection, powder, for solution • 20 mg • Intravenous • EU • Approved
  • Pepaxto
    Injection, powder, lyophilized, for solution • 20 mg/50mL • Intravenous • US • Approved
International Brands
  • Pepaxto — Oncopeptides AB

Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.
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