Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: antihistamines – H 1 antagonist, ATC code: R06A X27 
Mechanism of action
Desloratadine is a non-sedating, long-acting histamine antagonist with selective peripheral H 1 - receptor antagonist activity. After oral administration, desloratadine selectively blocks peripheral histamine H 1 -receptors because the substance is excluded from entry to the central nervous system.

Desloratadine has demonstrated antiallergic properties from in vitro studies. These include inhibiting the release of proinflammatory cytokines such as IL-4, IL-6, IL-8, and IL-13 from human mast cells/basophils, as well as inhibition of the expression of the adhesion molecule P-selectin on endothelial cells. The clinical relevance of these observations remains to be confirmed.

Clinical efficacy and safety

Paediatric population
Safety of Aerius syrup was demonstrated in three paediatric trials. Children, 1-11 years of age, who were candidates for antihistamine therapy received a daily desloratadine dose of 1.25 mg (1 through 5 years of age) or 2.5 mg (6 through 11 years of age). Treatment was well tolerated as documented by clinical laboratory tests, vital signs, and ECG interval data, including QTc. When given at the recommended doses, the plasma concentrations of desloratadine (see section 5.2) were comparable in the paediatric and adult populations. Thus, since the course of allergic rhinitis/chronic idiopathic urticaria and the profile of desloratadine are similar in adults and paediatric patients, desloratadine efficacy data in adults can be extrapolated to the paediatric population.
Efficacy of Aerius syrup has not been investigated in paediatric trials in children less than 12 years of age.

Adults and adolescents
In a multiple dose clinical trial, in adults and adolescents, in which up to 20 mg of desloratadine was administered daily for 14 days, no statistically or clinically relevant cardiovascular effect was observed.
In a clinical pharmacology trial, in adults and adolescents, in which desloratadine was administered to adults at a dose of 45 mg daily (nine times the clinical dose) for ten days, no prolongation of QTc interval was seen.

Desloratadine does not readily penetrate the central nervous system. In controlled clinical trials, at the recommended dose of 5 mg daily for adults and adolescents, there was no excess incidence of 
somnolence as compared to placebo. Aerius tablets given at a single daily dose of 7.5 mg to adults and adolescents did not affect psychomotor performance in clinical trials. In a single dose study performed in adults, desloratadine 5 mg did not affect standard measures of flight performance including exacerbation of subjective sleepiness or tasks related to flying.

In clinical pharmacology trials in adults, co-administration with alcohol did not increase the alcohol- induced impairment in performance or increase in sleepiness. No significant differences were found in the psychomotor test results between desloratadine and placebo groups, whether administered alone or with alcohol.

No clinically relevant changes in desloratadine plasma concentrations were observed in multiple-dose ketoconazole and erythromycin interaction trials.

In adult and adolescent patients with allergic rhinitis, Aerius tablets were effective in relieving symptoms such as sneezing, nasal discharge and itching, as well as ocular itching, tearing and redness, and itching of palate. Aerius effectively controlled symptoms for 24 hours. The efficacy of Aerius tablets has not been clearly demonstrated in trials with adolescent patients 12 through 17 years of age.

In addition to the established classifications of seasonal and perennial, allergic rhinitis can alternatively be classified as intermittent allergic rhinitis and persistent allergic rhinitis according to the duration of symptoms. Intermittent allergic rhinitis is defined as the presence of symptoms for less than 4 days per week or for less than 4 weeks. Persistent allergic rhinitis is defined as the presence of symptoms for 4 days or more per week and for more than 4 weeks.

Aerius tablets were effective in alleviating the burden of seasonal allergic rhinitis as shown by the total score of the rhino-conjunctivitis quality of life questionnaire. The greatest amelioration was seen in the domains of practical problems and daily activities limited by symptoms.

Chronic idiopathic urticaria was studied as a clinical model for urticarial conditions, since the underlying pathophysiology is similar, regardless of etiology, and because chronic patients can be more easily recruited prospectively. Since histamine release is a causal factor in all urticarial diseases, desloratadine is expected to be effective in providing symptomatic relief for other urticarial conditions, in addition to chronic idiopathic urticaria, as advised in clinical guidelines.

In two placebo-controlled six week trials in patients with chronic idiopathic urticaria, Aerius was effective in relieving pruritus and decreasing the size and number of hives by the end of the first dosing interval. In each trial, the effects were sustained over the 24 hour dosing interval. As with other antihistamine trials in chronic idiopathic urticaria, the minority of patients who were identified as non- responsive to antihistamines was excluded. An improvement in pruritus of more than 50 % was observed in 55 % of patients treated with desloratadine compared with 19 % of patients treated with placebo. Treatment with Aerius also significantly reduced interference with sleep and daytime function, as measured by a four-point scale used to assess these variables.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Desloratadine plasma concentrations can be detected within 30 minutes of desloratadine administration in adults and adolescents. Desloratadine is well absorbed with maximum concentration achieved after approximately 3 hours; the terminal phase half-life is approximately 27 hours. The degree of accumulation of desloratadine was consistent with its half-life (approximately 27 hours) and a once daily dosing frequency. The bioavailability of desloratadine was dose proportional over the range of 5 mg to 20 mg.

In a series of pharmacokinetic and clinical trials, 6 % of the subjects reached a higher concentration of desloratadine. The prevalence of this poor metaboliser phenotype was comparable for adult (6 %) and paediatric subjects 2- to 11-year old (6 %), and greater among Blacks (18 % adult, 16 % paediatric) than Caucasians (2 % adult, 3 % paediatric) in both populations.

In a multiple-dose pharmacokinetic study conducted with the tablet formulation in healthy adult subjects, four subjects were found to be poor metabolisers of desloratadine. These subjects had a C max concentration about 3-fold higher at approximately 7 hours with a terminal phase half-life of approximately 89 hours.
Similar pharmacokinetic parameters were observed in a multiple-dose pharmacokinetic study conducted with the syrup formulation in paediatric poor metaboliser subjects 2- to 11-year old diagnosed with allergic rhinitis. The exposure (AUC) to desloratadine was about 6-fold higher and the C max was about 3 to 4 fold higher at 3-6 hours with a terminal half-life of approximately 120 hours.
Exposure was the same in adult and paediatric poor metabolisers when treated with age-appropriate doses. The overall safety profile of these subjects was not different from that of the general population.
The effects of desloratadine in poor metabolizers < 2 years of age have not been studied.

In separate single dose studies, at the recommended doses, paediatric patients had comparable AUC and C max values of desloratadine to those in adults who received a 5 mg dose of desloratadine syrup.

Distribution
Desloratadine is moderately bound (83 % - 87 %) to plasma proteins. There is no evidence of clinically relevant active substance accumulation following once daily adult and adolescent dosing of desloratadine (5 mg to 20 mg) for 14 days.

In a single dose, crossover study of desloratadine, the tablet and the syrup formulations were found to be bioequivalent.

Biotransformation

The enzyme responsible for the metabolism of desloratadine has not been identified yet, and therefore, some interactions with other medicinal products cannot be fully excluded. Desloratadine does not inhibit CYP3A4 in vivo, and in vitro studies have shown that the medicinal product does not inhibit CYP2D6 and is neither a substrate nor an inhibitor of P-glycoprotein.

Elimination
In a single dose trial using a 7.5 mg dose of desloratadine, there was no effect of food (high-fat, high caloric breakfast) on the disposition of desloratadine. In another study, grapefruit juice had no effect on the disposition of desloratadine.

Renally impaired patients
The pharmacokinetics of desloratadine in patients with chronic renal insufficiency (CRI) was compared with that of healthy subjects in one single-dose study and one multiple dose study. In the single-dose study, the exposure to desloratadine was approximately 2 and 2.5-fold greater in subjects with mild to moderate and severe CRI, respectively, than in healthy subjects. In the multiple-dose study, steady state was reached after Day 11, and compared to healthy subjects the exposure to desloratadine was ~1.5-fold greater in subjects with mild to moderate CRI and ~2.5-fold greater in subjects with severe CRI. In both studies, changes in exposure (AUC and C max ) of desloratadine and 3-hydroxydesloratadine were not clinically relevant.