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The SARfaris: GPCR, Kinase, ADME

Friday, 3 September 2010

2010 New Drug Approval - Pt. XI - Alcaftadine (Lastacaft)

ATC code: 

The summer got in the way of a timely post on this new drug. On 28 July 2010, Alcaftadine was approved for the treatment of patients with allergic conjunctivitis as a 0.25% opthalmic solution.
This allergic reaction is most familiar in patients with hay fever but can also be caused by other allergens such as dust mites, moulds, perfumes etc. It causes red, itchy and watery eyes.
Allergic conjunctivitis is caused by a type I hypersensitivity reaction of the immune system. Antigenic epitopes of the allergen are detected by IgE antibodies which mediate the excessive activation of mast cells and basophils.  The symptoms of allergic conjunctivitis are mainly caused by the release of histamine from these activated immune cells. Histamine increases the permeability of blood vessels and stimulates the activity of immune cells, through a number of differing histamine receptors.

Alcaftadine and it's carboxylic acid metabolite (produced via a non P450 route) are antagonists of the H1 histamine receptor (Uniprot: P35367) and also inhibit histamine release.

Alcaftadine is administered topically as a 0.25% solution. In a pharmakokinetics study, the plasma CMAX of Alcaftadine is 60pg/mL and occurs after 15 minutes, the plasma CMAX of the active metabolite is 10pg/mL and occurs after one hour. Plasma protein binding (ppb) for Alcaftadine is 39.2%, and for the carboxylic acid metabolite is 62.7%. The elimination half-life of the metabolite is appoximately 2 hours. The presence of the aldehyde is an unusual chemical feature in Alcaftadine, since aldehydes are usually quite reactive, as would be expected this group is readily metabolized to a carboxylic acid.

The full prescribing information is here.

Adverse reactions may include eye irritation, eye redness, nasopharyngitis, headache and influenza.

IUPAC: 11-(1-methylpiperidin-4-ylidene)-5,6-dihydro
SMILES: CN1CCC(CC1)=C2c3ccccc3CCn4c(C=O)cnc24
InChI: 1S/C19H21N3O/c1-21-9-6-15(7-10-21)18-17-
Alcaftadine was developed by the Janssen Research Foundation and will be marketed in the US under the name Lastacaft by Vistakon Pharmaceuticals.

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