Ambrisentan

Ambrisentan (U.S. trade name Letairis; E.U. trade name Volibris; India trade name Pulmonext by MSN labs) is a drug indicated for use in the treatment of pulmonary hypertension.

Ambrisentan
Clinical data
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: X (High risk)
  • US: X (Contraindicated)
    Routes of
    administration    		Oral
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    BioavailabilityUndetermined
    Protein binding99%
    Elimination half-life15 hours (terminal)
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    ChemSpider
    UNII
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.184.855
    Chemical and physical data
    FormulaC22H22N2O4
    Molar mass378.421 g/mol g·mol−1
    3D model (JSmol)
      (verify)

    The peptide endothelin constricts muscles in blood vessels, increasing blood pressure. Ambrisentan, which relaxes those muscles, is an endothelin receptor antagonist, and is selective for the type A endothelin receptor (ETA).[1] Ambrisentan significantly improved exercise capacity (6-minute walk distance) compared with placebo in two double-blind, multicenter trials (ARIES-1 and ARIES-2).[2]

    Ambrisentan was approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency, and designated an orphan drug, for the treatment of pulmonary hypertension.[3][4][5][6][7]

    Recent Developments and Publications

    Last Updated 9/2/2015

    8/15/2015 Reprod. Toxicol.Endothelin receptor activation mediates strong pulmonary vasoconstriction and positive inotropic effect on the heart. These physiologic effects are vital for the development of the fetal cardiopulmonary system. As such, endothelin receptor antagonists such as Ambrisentan are teratogenic.[8]
    8/27/2015 NEJMAmbrisentan when used in combination therapy with Tadalafil was found to be more efficacious in treating treatment naive patients with WHO class II or III Pulmonary Arterial Hypertension than monotherapy using either drug.[9]

    Clinical uses

    Ambrisentan is indicated for the treatment of pulmonary arterial hypertension (WHO Group 1) in patients with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening.

    Birth defects

    Endothelin receptor activation mediates strong pulmonary vasoconstriction and positive inotropic effect on the heart. These physiologic effects are vital for the development of the fetal cardiopulmonary system. In addition to this, endothelin receptors are also known to play a role in neural crest cell migration, growth, and differentiation. As such, endothelin receptor antagonists such as Ambrisentan are known to be teratogenic.

    Ambrisentan has a high risk of liver damage, and of birth defects if a woman becomes pregnant while taking it. In the U.S., doctors who prescribe it, and patients who take it, must enroll in a special program, the LETAIRIS Education and Access Program (LEAP), to learn about those risks. Ambrisentan is available only through specialty pharmacies.

    References
    1. Vatter H, Seifert V (2006). "Ambrisentan, a non-peptide endothelin receptor antagonist". Cardiovasc Drug Rev. 24 (1): 63–76. doi:10.1111/j.1527-3466.2006.00063.x. PMID 16939634.
    2. Frampton JE (2011). "Ambrisentan". American Journal of Cardiovascular Drugs. 11 (4): 215–26. doi:10.2165/11207340-000000000-00000. PMID 21623643.
    3. Pollack, Andrew (2007-06-16). "Gilead's Drug Is Approved to Treat a Rare Disease". The New York Times. Archived from the original on May 24, 2013. Retrieved 2007-05-25.
    4. "U.S. Food and Drug Administration Approves Gilead's Letairis Treatment of Pulmonary Arterial Hypertension" (Press release). Gilead Sciences. 2007-06-15. Archived from the original on 2007-09-27. Retrieved 2007-06-16.
    5. "FDA Approves New Orphan Drug for Treatment of Pulmonary Arterial Hypertension" (Press release). Food and Drug Administration. 2007-06-15. Archived from the original on 23 June 2007. Retrieved 2007-06-22.
    6. "GlaxoSmithKline's Volibris (ambrisentan) receives authorisation from the European Commission for the treatment of Functional Class II and III Pulmonary Arterial Hypertension" (Press release). GlaxoSmithKline. 2008-04-25. Archived from the original on 2008-04-30. Retrieved 2008-04-29.
    7. Waknine, Yael (2005-05-09). "International Approvals: Ambrisentan, Oral-lyn, Risperdal". Medscape. Retrieved 2007-06-16.
    8. de Raaf MA, Beekhuijzen M, Guignabert C, Vonk Noordegraaf A, Bogaard HJ (2015). "Endothelin-1 receptor antagonists in fetal development and pulmonary arterial hypertension". Reproductive Toxicology. 56: 45–51. doi:10.1016/j.reprotox.2015.06.048. PMID 26111581.
    9. Galiè, Nazzareno; Barberà, Joan A.; Frost, Adaani E.; Ghofrani, Hossein-Ardeschir; Hoeper, Marius M.; McLaughlin, Vallerie V.; Peacock, Andrew J.; Simonneau, Gérald; Vachiery, Jean-Luc; Grünig, Ekkehard; Oudiz, Ronald J.; Vonk-Noordegraaf, Anton; White, R. James; Blair, Christiana; Gillies, Hunter; Miller, Karen L.; Harris, Julia H.N.; Langley, Jonathan; Rubin, Lewis J. (2015). "Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension". New England Journal of Medicine. 373 (9): 834–44. doi:10.1056/NEJMoa1413687. hdl:2445/97236. PMID 26308684.
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