Efficacy and tolerability of rupatadine at four times the recommended dose against histamine‐ and platelet‐activating factor‐induced flare responses and ex vivo platelet aggregation in healthy males

Summary Background  European guidelines recommend increasing H 1 ‐antihistamine doses up to fourfold in poorly responding patients with urticaria. Objectives  To assess the efficacy and tolerability of high‐dose rupatadine (40 mg) against platelet‐activating factor (PAF)‐ and histamine‐induced flare responses in human skin and to verify its anti‐PAF activity by assessing its inhibition of PAF‐induced platelet aggregation in the blood of subjects receiving rupatadine 40 mg. Methods  In the flare study, six male volunteers received a single dose of rupatadine 40 mg. Flares were induced before dosing and up to 96 h afterwards by intradermal PAF and histamine. In the e x vivo study, four male volunteers received an oral dose of rupatadine 40 mg and blood samples were taken 4 h afterwards. Platelet aggregation was assessed in platelet‐rich plasma by incubation for 5 min with PAF. Results  Rupatadine 40 mg reached maximal plasma levels of 15·1 ± 4·4 ng mL −1 at 1 h and its metabolite, desloratadine, 5·2 ± 0·9 ng mL −1 at 2 h. Neither was detectable at 12 h. Inhibition of histamine‐ and PAF‐induced flares was significant within 2 h, maximal at 6 h (87·8 ± 3·1% and 87·1 ± 2·5% inhibition, respectively, P  <   0·0001) and still statistically significant at 72 h. Rupatadine 40 mg inhibited PAF‐induced platelet aggregation ex vivo by 82 ± 9% ( P  =   0·023). A single oral dose of rupatadine 40 mg was well tolerated with mild transient somnolence being reported. Conclusions  A single dose of rupatadine at four times the recommended dose is well tolerated, highly effective for up to 72 h against PAF‐ and histamine‐induced dermal flares and has demonstrable PAF‐receptor antagonism ex vivo .