Aerius D-12 Mechanism of Action

Pharmacology: Desloratadine is a long acting tricyclic histamine antagonist with selective H1-receptor histamine antagonist activity. Receptor binding data indicates that at a concentration of 2 - 3 ng/ml (7 nanomolar), desloratadine shows significant interaction with the human histamine H1 receptor. Desloratadine has an antihistamine potency approximately 3.5 - 20 times greater than loratadine in vitro and 2.5 - 4 times greater than loratadine in animals. Desloratadine inhibited histamine release from human mast cells in vitro. Results of a radiolabeled tissue distribution study in rats and a radioligand H1-receptor binding study in guinea pigs showed that desloratadine did not readily cross the blood brain barrier.
Pseudoephedrine sulphate is an orally active sympathomimetic amine and exerts a decongestant action on the nasal mucosa. Pseudoephedrine sulphate is recognized as an effective agent for the relief of nasal congestion due to allergic rhinitis. Pseudoephedrine produces peripheral effects similar to those of ephedrine and central effects similar to, but less intense than, amphetamines. It has the potential for excitatory side effects.
Pharmacodynamics: Wheal and Flare: Human histamine skin wheal studies following single and repeated 5 mg doses of desloratadine have shown that the drug exhibits an antihistaminic effect by 1 hour; this activity may persist for as long as 24 hours. There was no evidence of histamine-induced skin wheal tachyphylaxis within the desloratadine 5 mg group over the 28-day treatment period.
Effects on QTc: In clinical trials for AERIUS D-12 Tablets, ECGs were recorded at baseline and endpoint within 1 to 6 hours after the last dose. The majority of ECGs were normal at both baseline and endpoint. No clinically meaningful changes were observed following treatment with AERIUS D-12 Tablets for any ECG parameter, including the QTc interval.
Pharmacokinetics: Absorption and Bioavailability: In a single dose pharmacokinetic study, the mean time to maximum plasma concentrations (T_max) for desloratadine occurred at approximately 4-5 hours post dose and mean peak plasma concentrations (C_max) and area under the concentration-time curve (AUC) of approximately 1.09 ng/mL and 31.6 ng⋅hr/mL, respectively, were observed. In another pharmacokinetic study, food and grapefruit juice had no effect on the bioavailability (C_max and AUC) of desloratadine. For pseudoephedrine, the mean T_max occurred at 6-7 hours post dose and mean peak plasma concentrations (C_max) and area under the concentration-time curve (AUC) of approximately 263 ng/mL and 4588 ng·hr/mL, respectively, were observed. Food had no effect on the bioavailability (C_max and AUC) of desloratadine or pseudoephedrine.
Following oral administration of AERIUS D-12 Tablets dosed twice daily for 14 days in normal healthy volunteers, steady state conditions were reached on day 10 for desloratadine, 3-hydroxydesloratadine and pseudoephedrine. For desloratadine, mean steady state peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC 0-12hrs) of approximately 1.7 ng/mL and 16 ng⋅hr/mL were observed, respectively. For pseudoephedrine, mean steady state peak plasma concentrations (C_max) and AUC (0-12 hrs) of 459 ng/mL and 4658 ng⋅hr/mL were observed.
Distribution: Desloratadine and 3-hydroxydesloratadine are approximately 82% to 87% and 85% to 89%, bound to plasma proteins, respectively. Protein binding of desloratadine and 3-hydroxydesloratadine was unaltered in subjects with impaired renal function.
Metabolism: Desloratadine (a major metabolite of loratadine) is extensively metabolized to 3-hydroxydesloratadine, an active metabolite, which is subsequently glucuronidated. Analysis of plasma desloratadine and 3-hydroxydesloratadine concentrations showed similar T_max and half-life values for both compounds.
The enzyme(s) responsible for the formation of 3-hydroxydesloratadine have not been identified.
Data from clinical trials with desloratadine indicate that a subset of the general population has a decreased ability to form 3-hydroxydesloratadine, and are poor metabolizers of desloratadine. In pharmacokinetic studies (n=3748), approximately 6% of subjects were poor metabolizers of desloratadine (defined as a subject with an AUC ratio of 3-hydroxydesloratadine to desloratadine less than 0.1, or a subject with a desloratadine half-life exceeding 50 hours). These pharmacokinetic studies included subjects between the ages of 2 and 70 years, including 977 subjects aged 2-5 years, 1575 subjects aged 6-11 years, and 1196 subjects aged 12-70 years. There was no difference in the prevalence of poor metabolizers across age groups. The frequency of poor metabolizers was higher in Blacks (17%, n=988) as compared to Caucasians (2%, n=1462) and Hispanics (2%, n=1063). The median exposure (AUC) to desloratadine in the poor metabolizers was approximately 6-fold greater than in the subjects who are not poor metabolizers. Subjects who are poor metabolizers of desloratadine cannot be prospectively identified and will be exposed to higher levels of desloratadine following dosing with the recommended dose of desloratadine. In these studies, no overall differences in safety were observed between poor metabolizers and normal metabolizers.
Pseudoephedrine alone, is incompletely metabolized in the liver by N-demethylation to an inactive metabolite. The drug and its metabolite are excreted in the urine. About 55-96% of an administered dose of pseudoephedrine hydrochloride is excreted unchanged in the urine.
Elimination: Following single dose administration of AERIUS D-12 Tablets, the mean plasma elimination half-life of desloratadine was approximately 24 hours.
When administered alone, the mean elimination half-life of pseudoephedrine is approximately 4-6 hours which is dependent on urine pH. The elimination half-life is decreased at urine pH lower than 6 and may be increased at urine pH higher than 8.