Telfast Mechanism of Action

Pharmacology: Pharmacodynamics: Fexofenadine hydrochloride is a non-sedating H1 antihistamine. Fexofenadine is a pharmacologically active metabolite of terfenadine.
Human histamine wheal and flare studies the following single and twice daily doses of fexofenadine hydrochloride demonstrate that the drug exhibits an antihistaminic effect beginning within one hour, achieving maximum at 6 hours and lasting 24 hours. There was no evidence of tolerance to these effects after 28 days of dosing. A positive dose-response relationship between doses of 10 mg to 130 mg taken orally was found to exist. In this model of antihistaminic activity, it was found that doses of at least 130 mg were required to achieve a consistent effect that was maintained over a 24 hour period. Maximum inhibition in skin wheal and flare areas were greater than 80%.
No significant differences in QTc intervals were observed in seasonal allergic rhinitis patients given fexofenadine hydrochloride up to 240 mg twice daily for 2 weeks when compared to placebo. Also, no significant change in QTc intervals was observed in healthy subjects given fexofenadine hydrochloride up to 60 mg twice daily for 6 months, 400 mg twice daily for 6.5 days and 240 mg once daily for 1 year, when compared to placebo. Fexofenadine at concentrations 32 times greater than the therapeutic concentration in man had no effect on the delayed rectifier K+ channel cloned from human heart.
Fexofenadine hydrochloride (5-10 mg/kg po) inhibited antigen induced bronchospasm in sensitized guinea pigs and inhibited histamine release at supratherapeutic concentrations (10-100 um) from peritoneal mast cells.
Pharmacokinetics: Fexofenadine hydrochloride is rapidly absorbed into the body following oral administration, with Tmax occurring at approximately 1-3 hours post dose. The mean Cmax value was approximately 427 mg/mL (following the administration of 120 mg dose daily) or 494 ng/mL (following the administration of a 180 mg dose once daily).
Fexofenadine is 60-70% plasma protein bound. Fexofenadine undergoes negligible metabolism, (hepatic or non-hepatic) as it was the only major compound identified in urine and faeces of animals and man. The plasma concentrations profiles of fexofenadine follow a bi-exponential decline with a terminal elimination half-life ranging from 11 to 15 hours after multiple dosing. The single and multiple dose pharmacokinetics of fexofenadine are linear for oral doses up to 120 mg BID. A dose of 240 mg BID produced slightly greater than proportional increase (8.8%) in steady state area under the curve, indicating that fexofenadine pharmacokinetics are practically linear at these doses. The major route of elimination is believed to be via biliary excretion while up to 10% if ingested dose is excreted unchanged through the urine.
Toxicology: Preclinical safety data: Dogs tolerated 450 mg/kg administered twice daily for 6 months and showed no toxicity other than occasional emesis. Also, in single dose dog and rodent studies, no treatment-related gross findings were observed following necropsy. Radiolabelled fexofenadine hydrochloride in tissue distribution studies of the rat indicated that fexofenadine did not cross the blood brain barrier. Fexofenadine hydrochloride was found to be non-mutagenic in various in vitro and in vivo mutagenicity tests. The carcinogenic potential of fexofenadine hydrochloride was assessed using terfenadine studies with supporting pharmacokinetic studies showing fexofenadine hydrochloride exposure (via plasma AUC values). No evidence of carcinogenicity was observed in rats and mice given terfenadine (up to 150 mg/kg/day). In a reproductive toxicity study in mice, fexofenadine hydrochloride did not impair fertility, was not teratogenic and did not impair pre- or postnatal development.