Ebastine

Ebastine has been shown to produce a rapid and long-lasting inhibition of histamine-induced effect and to have a strong affinity towards H₁-receptors.

Following oral administration, neither ebastine or its metabolites cross the blood brain barrier. This characteristic is consistent with the low sedative profile seen in the results of experiments studying the effects of ebastine on the central nervous system.

In vitro and in vivo data demonstrate that ebastine is a potent, long-lasting and highly selective histamine H₁–receptor antagonist devoid of untoward CNS actions and anticholinergic effects.

Pharmacodynamic properties

Histamine skin wheal studies have shown a statistically and clinically significant anti-histamine effect beginning at 1 hour and lasting in excess of 48 hours. After the discontinuation of the administration of a 5 day course treatment with ebastine, the anti-histamine activity remained apparent for more than 72 hours. This activity parallels the plasma levels of the main active acid metabolite, carebastine.

After repeated administration, inhibition of the peripheral receptors remained at a constant level, without tachyphylaxis. These results suggest that ebastine at a dose of at least 10 mg produces a rapid, intense and long-lasting inhibition of peripheral H₁ histamine receptors, consistent with a once-a-day administration.

In a single dose trial, the oral lyophilisate formulation was well tolerated as documented by standard safety laboratory tests, physical examinations, vital signs and ECG. Ebastine oral lyophilisate was found to be bioequivalent to the film-coated tablet formulation of ebastine. Therefore, the efficacy of ebastine oral lyophilisate is expected to be the same as that of the film-coated tablet formulation.

Sedation was studied through pharmaco-EEG, cognitive performance, visual-motor coordination tests and subjective estimates. There was no significant increase of sedation at the recommended dose. These results are consistent with those from double-blind clinical trials; the incidence of sedation is comparable between placebo and ebastine.

Cardiac effects of ebastine have been thoroughly investigated, following single doses from 2.5 to 50 mg and multiple doses from 10 to 80 mg/kg/day for 7 days, with no evidence of an effect on QT corrected interval.

Ebastine is rapidly absorbed and undergoes extensive first pass metabolism following oral administration. Ebastine is almost totally converted to the pharmacologically active acid metabolite, carebastine.

After a single 10 mg oral dose, peak plasma levels of the metabolite occur at 2.6 to 4 hours and achieve levels of 80 to 100 ng/ml. The half-life of the acid metabolite is between 15 and 19 hours with 66% of the drug being excreted in the urine mainly as conjugated metabolites. Following the repeated administration of 10 mg once-daily, steady state was achieved in 3 to 5 days with peak plasma levels ranging from 130 to 160 ng/ml.

The pharmacokinetics of ebastine, as well as that of its active metabolite carebastine were found to be linear in the recommended therapeutic dose range of 10 to 20 mg.

In vitro studies with human liver microsomes show that ebastine is metabolised to carebastine predominantly via the CYP3A4 pathway. Concurrent administration of ebastine with ketoconazole or erythromycin (both CYP3A4 inhibitors) to healthy volunteers was associated with significantly increased plasma concentrations of ebastine and carebastine.

Both ebastine and carebastine are highly protein bound, >97%.

In elderly subjects, no statistically significant changes were observed in the pharmacokinetics compared to those of young adult volunteers.

In patients with several degrees of renal insufficiency treated with daily doses of 20 mg ebastine, as well as in patients with mild to moderate hepatic insufficiency treated with 20 mg ebastine, or with severe hepatic insufficiency treated with 10 mg ebastine, plasma concentrations of ebastine and carebastine attained during the first and fifth day of treatment were similar to those attained in healthy volunteers. Thus, the pharmacokinetic profile of ebastine and its metabolites do not change significantly in patients with several degrees of hepatic or renal insufficiency.

In a single-dose crossover study of ebastine oral lyophilisate versus ebastine film-coated tablets, the formulations were found to be bioequivalent. Water intake after ebastine oral lyophilisate had no effect on the disposition of ebastine.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.