ASTEPRO Clinical Pharmacology
Azelastine hydrochloride, a phthalazinone derivative, exhibits histamine H1-receptor antagonist activity in isolated tissues, animal models, and humans. ASTEPRO Nasal Spray is administered as a racemic mixture with no difference in pharmacologic activity noted between the enantiomers in in vitro studies.1
The major metabolite, desmethylazelastine, also possesses H1 -receptor antagonist activity.
Pharmacokinetics1
Absorption:
After intranasal administration of 2 sprays per nostril (548 mcg total dose) of ASTEPRO, the mean azelastine peak plasma concentration (Cmax) is 200 pg/mL, the mean extent of systemic exposure (AUC) is 5122 pg•hr/ml and the median time to reach Cmax (tmax) is 3 hours. Azelastine hydrochloride administered intranasally at doses above two sprays per nostril twice daily for 29 days resulted in greater than proportional increases in Cmax and AUC for azelastine. The systemic bioavailability of azelastine hydrochloride is approximately 40% after intranasal administration.
Distribution:
Based on intravenous and oral administration, the steady-state volume of distribution of azelastine is 14.5 L/kg. In vitro studies with human plasma indicate that the plasma protein binding of azelastine and its metabolite, desmethylazelastine, are approximately 88% and 97%, respectively.
Metabolism:
Azelastine is oxidatively metabolized to the principal active metabolite, desmethylazelastine, by the cytochrome P450 enzyme system. The specific P450 isoforms responsible for the biotransformation of azelastine have not been identified. After a single-dose, intranasal administration of ASTEPRO Nasal Spray, the mean desmethylazelastine Cmax is 23 pg/mL, the AUC is 2131 pg•hr/mL and the median tmax is 24 hours. After intranasal dosing of azelastine to steady-state, plasma concentrations of desmethylazelastine range from 20-50% of azelastine concentrations.
Elimination:
Following intranasal administration of ASTEPRO Nasal Spray, the elimination half-life of azelastine is 22 hours while that of desmethylazelastine is 52 hours. Approximately 75% of an oral dose of radiolabeled azelastine hydrochloride was excreted in the feces with less than 10% as unchanged azelastine.
1ASTEPRO package insert. Somerset, NJ: Meda Pharmaceuticals Inc; 2008.
