Peringatan Keamanan

Lasofoxifene increases the risk of venous thromboembolism driven by increased risk of deep vein thrombosis. Other adverse effects include hot flushes, muscle spasms and vaginal bleeding.

Lasofoxifene

DB06202

small molecule approved investigational

Deskripsi

Lasofoxifene is a non-steroidal 3rd generation selective estrogen receptor modulator (SERM) that selectively binds to both ER? and ER? with high affinity. It is a naphthalene derivative marketed for prevention and treatment of osteoporosis and for the treatment of vaginal atrophy. It was initially developed as Oporia by Pfizer as a treatment for postmenopausal osteoporosis and vaginal atrophy, in which were both rejected for approval by FDA. Later Fablyn was developed as a result of a research collaboration between Pfizer and Ligand Pharmaceuticals with a newly submitted New Drug Application in 2008. It gained approval by European Commission in March 2009. Ligand Pharmaceuticals signed a license agreement with Sermonix Pharmaceuticals for the development and commercialization of oral lasofoxifene in the USA.

Struktur Molekul 2D

Berat 413.5512
Wujud solid

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

Profil Farmakokinetik

Waktu Paruh (Half-Life) Elimination half-life is approximately 6 days [A19178].
Volume Distribusi The apparent volume of distribution in postmenopausal women is 1350L [L762].
Klirens (Clearance) The apparent oral clearance (CL/F) of lasofoxifene in postmenopausal women is approximately 6.6 l/hr[L762].

Absorpsi

Peak plasma concentrations (Cmax) were reached in about 6.0 to 7.3 hours A19181. Displays higher oral bioavailability compared to other SERMs with increased resistance to intestinal glucuronidation due to nonpolar tetrahydronaphthalene structure A4024. In a comparative study in the rat, lasofoxifene showed bioavailability of 62% A19178.

Metabolisme

Phase I oxidation via hepatic CYP3A4/CYP3A5 and CYP2D6 accounts for nearly half of total metabolism of lasofoxifene. Phase II conjugation reactions include glucuronidation and sulfation. Its glucuronidation is catalyzed by UGTs that are expressed in both the liver (UGT1A1, UGT1A3, UGT1A6, and UGT1A9) and the intestine (UGT1A8 and UGT1A10). Further metabolites of lasofoxifene detected in plasma are the glucuronide of a hydroxylated metabolite, and the methylated catechols L762.

Rute Eliminasi

Primarily fecal excretion and secondarily renal elimination as mainly metabolites, with less than 2% excreted in urine as unchanged parent drug.

Interaksi Obat

2 Data
Ospemifene The risk or severity of adverse effects can be increased when Lasofoxifene is combined with Ospemifene.
Fluoroestradiol F-18 Lasofoxifene may decrease effectiveness of Fluoroestradiol F-18 as a diagnostic agent.

Target Protein

Fusion glycoprotein F0 F
Estrogen receptor ESR1
Estrogen receptor beta ESR2
Cannabinoid receptor 2 CNR2

Referensi & Sumber

Artikel (PubMed)
  • PMID: 16916275
    Gennari L, Merlotti D, Martini G, Nuti R: Lasofoxifene: a third-generation selective estrogen receptor modulator for the prevention and treatment of osteoporosis. Expert Opin Investig Drugs. 2006 Sep;15(9):1091-103.
  • PMID: 18367319
    Crabtree JS, Peano BJ, Zhang X, Komm BS, Winneker RC, Harris HA: Activity of three selective estrogen receptor modulators on hormone-dependent responses in the mouse uterus and mammary gland. Mol Cell Endocrinol. 2008 Jun 11;287(1-2):40-6. doi: 10.1016/j.mce.2008.01.027. Epub 2008 Feb 12.
  • PMID: 17456742
    Vajdos FF, Hoth LR, Geoghegan KF, Simons SP, LeMotte PK, Danley DE, Ammirati MJ, Pandit J: The 2.0 A crystal structure of the ERalpha ligand-binding domain complexed with lasofoxifene. Protein Sci. 2007 May;16(5):897-905.
  • PMID: 20169039
    Gennari L, Merlotti D, Nuti R: Selective estrogen receptor modulator (SERM) for the treatment of osteoporosis in postmenopausal women: focus on lasofoxifene. Clin Interv Aging. 2010 Feb 2;5:19-29.
  • PMID: 20694069
    Gennari L, Merlotti D, De Paola V, Nuti R: Lasofoxifene: Evidence of its therapeutic value in osteoporosis. Core Evid. 2010 Jun 15;4:113-29.
  • PMID: 19898646
    Lewiecki EM: Lasofoxifene for the prevention and treatment of postmenopausal osteoporosis. Ther Clin Risk Manag. 2009;5:817-27. Epub 2009 Nov 2.
  • PMID: 23168292
    Nelson ER, Wardell SE, McDonnell DP: The molecular mechanisms underlying the pharmacological actions of estrogens, SERMs and oxysterols: implications for the treatment and prevention of osteoporosis. Bone. 2013 Mar;53(1):42-50. doi: 10.1016/j.bone.2012.11.011. Epub 2012 Nov 17.
  • PMID: 22853318
    Hadji P: The evolution of selective estrogen receptor modulators in osteoporosis therapy. Climacteric. 2012 Dec;15(6):513-23. doi: 10.3109/13697137.2012.688079. Epub 2012 Aug 1.
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Contoh Produk & Brand

Produk: 4 • International brands: 1
Produk
  • Fablyn
    Tablet, film coated • 500 μg • Oral • EU
  • Fablyn
    Tablet, film coated • 500 μg • Oral • EU
  • Fablyn
    Tablet, film coated • 500 μg • Oral • EU
  • Fablyn
    Tablet, film coated • 500 μg • Oral • EU
International Brands
  • Oporia — Pfizer

Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.
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