Ajalorin Mechanism of Action



AJ Research & Pharma


AJ Research & Pharma
Full Prescribing Info
Pharmacotherapeutic group: Antihistamines - H1 antagonist. ATC-code: R06A X27.
Pharmacology: Pharmacodynamics: Mechanism of action: Desloratadine is a non-sedating, long-acting histamine antagonist with selective peripheral H1-receptor antagonist activity. After oral administration, desloratadine selectively blocks peripheral histamine H1-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: In a multiple dose clinical trial, desloratadine orodispersible tablets were well tolerated. At the recommended dose, desloratadine 5 mg orodispersible tablet was found to be bioequivalent to the 5 mg conventional tablet formulation of desloratadine. Therefore, the efficacy of desloratadine orodispersible tablet is expected to be the same as with the desloratadine tablet formulation.
In a multiple dose clinical trial, 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 which desloratadine was administered at a dose of 45 mg daily (nine times the clinical dose) for ten days, no prolongation of QTc interval was seen.
No clinically relevant changes in desloratadine plasma concentrations were observed in multiple-dose ketoconazole and erythromycin interaction trials.
Desloratadine does not readily penetrate the central nervous system. In clinical trials, at the recommended dose of 5 mg daily, there was no excess incidence of somnolence as compared to placebo. Desloratadine tablets given at a single daily dose of 7.5 mg 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, 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.
In patients with allergic rhinitis, desloratadine tablets was effective in relieving symptoms such as sneezing, nasal discharge and itching, as well as ocular itching, tearing and redness, and itching of palate. Desloratadine tablets effectively controlled symptoms for 24 hours.
Paediatric population: The efficacy of desloratadine tablets have 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.
Desloratadine was 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, desloratadine 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 nonresponsive 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 desloratadine also significantly reduced interference with sleep and daytime function, as measured by a four-point scale used to assess these variables.
Pharmacokinetics: Absorption: Desloratadine plasma concentrations can be detected within 30 minutes of administration. 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; however, the safety profile of these subjects was not different from that of the general population.
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 Cmax concentration about 3-fold higher at approximately 7 hours with a terminal phase half-life of approximately 89 hours.
Distribution: Desloratadine is moderately bound (83 % - 87 %) to plasma proteins. There is no evidence of clinically relevant medicine accumulation following once daily dosing of desloratadine (5 mg to 20 mg) for 14 days.
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.
In single-dose crossover studies of desloratadine 5 mg orodispersible tablets with desloratadine 5 mg conventional tablets or desloratadine 5 mg oral lyophilisate, the formulations were bioequivalent.
Desloratadine 2.5 mg tablets has not been evaluated in paediatric patients however in conjunction with the dose finding studies in paediatrics, the pharmacokinetics data for desloratadine orodispersible tablets supports the use of the 2.5 mg dose in paediatric patients 6 to 11 years of age.
Elimination: The presence of food prolongs Tmax for desloratadine from 2.5 to 4 hours and Tmax for 3-OH-desloratadine from 4 to 6 hours. In a separate study, grapefruit juice had no effect on the disposition of desloratadine. Water had no effect on the bioavailability of desloratadine orodispersible tablets.
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 Cmax) of desloratadine and 3-hydroxydesloratadine were not clinically relevant.
Toxicology: Pre-clinical Safety Data: Desloratadine is the primary active metabolite of loratadine. Non-clinical studies conducted with desloratadine and loratadine demonstrated that there are no qualitative or quantitative differences in the toxicity profile of desloratadine and loratadine at comparable levels of exposure to desloratadine.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. The collective analysis of preclinical and clinical irritation studies for the orodispersible tablet indicate that this formulation in unlikely to pose risk for local irritation with clinical use. The lack of carcinogenic potential was demonstrated in studies conducted with desloratadine and loratadine.
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