Rupafin Mechanism of Action

Pharmacotherapeutic group: other antihistamines for systemic use. ATC code: R06A X28.
Pharmacology: Pharmacodynamics: Rupatadine is a second-generation antihistamine, long-acting histamine antagonist, with selective peripheral H₁-receptor antagonist activity. Some of the metabolites (desloratadine and its hydroxylated metabolites) retain an antihistaminic activity and may partially contribute to the overall efficacy of the drug.
Tablet: Chronic idiopathic urticaria was studied as a clinical model for urticaria 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, Rupatadine is expected to be effective in providing symptomatic relief for other urticarial conditions, in addition to chronic idiopathic urticaria, as advised in clinical guidelines.
Oral solution: In vitro studies with rupatadine at high concentration have shown an inhibition of the degranulation of mast cells induced by immunological and non-immunological stimuli as well as the release of cytokines, particularly of the TNF_α in human mast cells and monocytes. The clinical relevance of the observed experimental data remains to be confirmed.
Rupatadine oral solution had a similar pharmacokinetic profile in children between 6-11 years to that in adults (> 12 years): a pharmacodynamic effect was also observed (suppression of the wheal area, antihistamine effect) after 4 weeks of treatment. A randomised, double-blind and placebo-controlled confirmatory study in children with persistent allergic rhinitis aged 6 to 11 years, showed that rupatadine oral solution had a better profile in the reduction of nasal symptoms (rhinorrhea and itchy nose mouth throat and/or ears) than placebo in children with persistent allergic rhinitis after 4 and 6 weeks of treatment. Furthermore, a significant improvement in quality of life was also observed throughout the study in comparison with placebo.
Chronic spontaneous urticaria was studied as a clinical model to assess the efficacy of anti-H₁ compounds for all urticarial conditions, since the underlying pathophysiology is similar, regardless of etiology, and basically these chronic patients can be more easily recruited into a clinical study. Urticaria is a mast cell-driven disease and histamine and other mediators (PAF and cytokines) are the principal mediators to develop all urticarial lesions. Since rupatadine has capacity to block the release of histamine and other inflammatory mediators, it is expected to be effective treatment in providing symptomatic relief for other urticarial conditions, in addition to chronic spontaneous urticaria, as recommended in clinical guidelines.
The efficacy of rupatadine oral solution in chronic spontaneous urticaria in children aged 2-11 years has been demonstrated in a multicentre, randomized, active- and placebo-controlled study. Overall, 206 children were included. Of them, 113 were between 2-5 years and 93 of them were between 6-11 years. Children were treated with rupatadine (n=66), placebo (n=69) or desloratadine (n=71). Rupatadine dose administered was 2.5 mg in children weighting up to 25 kg and 5 mg in children weighting over 25 kg. Desloratadine dose administered was 1.25 mg in children weighting up to 25 kg and 2.5 mg in children weighting over 25 kg. A statistically significant improvement versus placebo was demonstrated in the mean change in weekly urticaria activity score (UAS7; comprising hives and pruritus), the main endpoint, evaluated after 6 weeks of treatment (rupatadine -11.77 vs. placebo -5.55; p <0.001). The mean percent reduction in the weekly number of hives at study endpoint versus baseline was 56.7% with rupatadine, 49.4% with desloratadine and 22.7% with placebo. The mean percent reduction in pruritus at study endpoint versus baseline was 56.8% with rupatadine, 46.7% with desloratadine and 33.4% with placebo. Both active treatments (rupatadine and desloratadine) achieved statistically significant greater improvements than placebo in the reduction in hives and pruritus, while there were not statistically significant differences between the active treatments regarding these outcomes. The percentage of patient responders of more than 50% in weekly urticaria activity score (UAS7 scale; urticaria and pruritus) was observed in 61% of children treated with rupatadine compared with 36% of children treated with placebo and 54% of children treated with desloratadine.
Clinical trials in volunteers (n=375) and patients (n=2650) with allergic rhinitis and chronic idiopathic urticaria did not show significant effect on the electrocardiogram when rupatadine tablets was administered at doses ranging from 2 mg to 100 mg.
The European Medicines Agency has waived the obligation to submit the results of studies with Rupafin oral solution in all subsets of the paediatric population in allergic rhinitis and chronic urticaria.
Pharmacokinetics: Tablet: Rupatadine is rapidly absorbed after oral administration, with a t_max of approximately 0.75 hours after intake. The mean C_max was 2.6 ng/mL after a single oral dose of 10 mg and 4.6 ng/mL after a single oral dose of 20 mg. Pharmacokinetics of rupatadine was linear for a dose between 10 and 40 mg. After a dose of 10 mg once a day for 7 days, the mean C_max was 3.8 ng/mL. The plasma concentration followed a bi-exponential drop-off with a mean elimination half-life of 5.9 hours. The binding-rate of Rupatadine (as fumarate) (Rupafin) to plasma proteins was 98.5-99%.
As rupatadine has never been administered to humans by intravenous route, no data is available on its absolute bioavailability.
Effect of the intake of food: Intake of food increased the systemic exposure (AUC) to rupatadine by about 23%. The exposure to one of its active metabolites and to the main inactive metabolite was practically the same (reduction of about 5% and 3% respectively). The time taken to reach the maximum plasma concentration (t_max) of rupatadine was delayed by 1 hour. The maximum plasma concentration (C_max) was not affected by food intake. These differences had no clinical significance.
Metabolism and elimination: In a study of excretion in humans (40 mg of ¹⁴C-rupatadine), 34.6% of the radioactivity administered was recovered in urine and 60.9% in feces collected over 7 days. Rupatadine undergoes considerable pre-systemic metabolism when administered by oral route. The amounts of unaltered active substance found in urine and feces were insignificant. This means that rupatadine is almost completely metabolized. In vitro metabolism studies in human liver microsomes indicate that rupatadine is mainly metabolized by the cytochrome P450 (CYP 3A4).
Oral solution: Paediatric population: In the subgroup of children 2-5 and 6-11 years old, rupatadine was rapidly absorbed and the mean C_max was of 1.9 and 2.5 ng/ml after repeated oral dose, respectively. In term of exposition, the mean total area under the curve (AUC) value was 10.4 ng.h/ml in children 2-5 years and 10.7 ng·h/ml in children 6-11 years. All these values are similar to those obtained in adults and adolescents.
The mean elimination half-life of rupatadine in children 2-5 years was 15.9 h and in children 6- 11 years was 12.3 h, which are longer than that reported with tablets in adults and adolescents.
Effect of the intake of food: No interaction food study has been performed with rupatadine oral solution. The influence of food was performed in adults and adolescents with rupatadine 10 mg tablets. Intake of food increased the systemic exposure (AUC) to rupatadine by about 23%. The maximum plasma concentration (C_max) was not affected by food intake. These differences had no clinical significance.
Metabolism and elimination: In a study of excretion in adults, 34.6% of rupatadine administered was recovered in urine and 60.9% in faeces collected over 7 days. Rupatadine undergoes considerable pre-systemic metabolism when administered by oral route. The amounts of unaltered active substance found in urine and faeces were insignificant. This means that rupatadine is almost completely metabolised. Roughly, the active metabolites desloratadine and other hydroxylated derivatives accounted for 27% and 48%, respectively, of the total systemic exposure of the active substances. In vitro metabolism studies in human liver microsomes indicate that rupatadine is mainly metabolised by the cytochrome P450 (CYP 3A4).
Toxicology: Preclinical safety data: Oral solution: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.
More than 100 times the clinically recommended dose in adults (10 mg) of rupatadine did neither extend the QTc or QRS interval nor produce arrhythmia in various species of animals such as rats, guinea pigs and dogs. Rupatadine and one of its main active metabolites in humans, 3-hydroxydesloratadine, did not affect the cardiac action potential in isolated dog Purkinje fibres at concentrations at least 2000 times greater than the C_max reached after the administration of a dose of 10 mg in humans. In a study that evaluated the effect on cloned human HERG channel, rupatadine inhibited that channel at a concentration 1685 times greater than the C_max obtained after the administration of 10 mg of rupatadine. Studies of tissue distribution in rats with radiolabelled rupatadine showed that rupatadine does not accumulate in heart tissue.
In the rat, a significant reduction of male and female fertility occurred at the high dose of 120 mg/kg/day, providing C_max 268 times those measured in humans at the therapeutic dose (10 mg/day). Foetal toxicity (growth delay, incomplete ossification, minor skeletal findings) was reported in rats at maternotoxic dose-levels only (25 and 120 mg/kg/day). In rabbits, no evidence of developmental toxicity was noted at doses up to 100 mg/kg. The developmental No Adverse Effect Levels were determined at 5 mg/kg/day in rats and 100 mg/kg/day in rabbits, yielding C_max 45 and 116 times higher, respectively, than those measured in humans at the therapeutic dose (10 mg/day).