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.[1][2]

Ambrisentan
Clinical data
Trade namesLetairis, Volibris, Pulmonext
AHFS/Drugs.comMonograph
MedlinePlusa612023
License data
Pregnancy
category
  • AU: X (High risk)
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: ℞-only
  • EU: Rx-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityUndetermined
Protein binding99%
Elimination half-life15 hours (terminal)
Identifiers
  • (2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.184.855
Chemical and physical data
FormulaC22H22N2O4
Molar mass378.428 g·mol−1
3D model (JSmol)
  • O=C(O)[C@@H](Oc1nc(cc(n1)C)C)C(OC)(c2ccccc2)c3ccccc3
  • InChI=1S/C22H22N2O4/c1-15-14-16(2)24-21(23-15)28-19(20(25)26)22(27-3,17-10-6-4-7-11-17)18-12-8-5-9-13-18/h4-14,19H,1-3H3,(H,25,26)/t19-/m1/s1 checkY
  • Key:OUJTZYPIHDYQMC-LJQANCHMSA-N checkY
  (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).[3] Ambrisentan significantly improved exercise capacity (6-minute walk distance) compared with placebo in two double-blind, multicenter trials (ARIES-1 and ARIES-2).[4] Like all endothelin receptor antagonists, Ambrisentan is contraindicated in pregnant women as well as those who are trying to become pregnant, due to the potential for teratogenic effects on the fetus.[5] Patients who are on the Ambrisentan must enroll in the Ambrisentan (Letairis) REMS Program.[6]

Ambrisentan was approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), and designated an orphan drug, for the treatment of pulmonary hypertension.[7][8][9][10]

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.

Mechanism of action

Ambrisentan is a drug that blocks endothelin, an endogenous hormone found in higher quantities in patients with pulmonary arterial hypertension. Endothelin binds to two receptors, ETA and ETB. ETA is responsible for cell growth in the vessels as well as vasoconstriction, while ETB plays a role in vasodilation, endothelin 1 clearance, and antiproliferation of cells.

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.[11] Ambrisentan is available only through specialty pharmacies.

Hepatic impairment

Ambrisentan is not recommended in patients with moderate or severe hepatic impairment. The medication should also be discontinued if the liver aminotransferase enzymes for the patients are increased more than fivefold, or if the elevations are more than twofold and are accompanied by changes in bilirubin.[12]

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.[13]
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.[14]

References
  1. "Letairis- ambrisentan tablet, film coated". DailyMed. 4 September 2019. Retrieved 18 April 2020.
  2. "Ambrisentan Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. 7 January 2019. Retrieved 18 April 2020.
  3. Vatter H, Seifert V (2006). "Ambrisentan, a non-peptide endothelin receptor antagonist". Cardiovascular Drug Reviews. 24 (1): 63–76. doi:10.1111/j.1527-3466.2006.00063.x. PMID 16939634.
  4. Frampton JE (August 2011). "Ambrisentan". American Journal of Cardiovascular Drugs. 11 (4): 215–26. doi:10.2165/11207340-000000000-00000. PMID 21623643.
  5. Galiè N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, et al. (June 2008). "Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2". Circulation. 117 (23): 3010–9. doi:10.1161/CIRCULATIONAHA.107.742510. PMID 18506008.
  6. "Clinical Results | Letairis® (ambrisentan)". www.letairis.com. Retrieved 24 October 2021.
  7. "Drug Approval Package: Letairis (Ambrisentan) NDA #022081". U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 18 April 2020.
  8. "Volibris EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 18 April 2020.
  9. "Ambrisentan Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). Retrieved 18 April 2020.
  10. Pollack A (16 June 2007). "Gilead's Drug Is Approved to Treat a Rare Disease". The New York Times. Archived from the original on 24 May 2013. Retrieved 16 June 2007.
  11. "Clinical Results | Letairis® (ambrisentan)". www.letairis.com. Retrieved 24 October 2021.
  12. "Clinical Results | Letairis (ambrisentan)". www.letairis.com. Retrieved 24 October 2021.
  13. 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.
  14. Galiè N, Barberà JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV, et al. (August 2015). "Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension". The New England Journal of Medicine. 373 (9): 834–44. doi:10.1056/NEJMoa1413687. hdl:2445/97236. PMID 26308684.
  • "Ambrisentan". Drug Information Portal. U.S. National Library of Medicine.
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