A randomized, double-blind, crossover comparison among cetirizine, levocetirizine, and ucb 28557 on histamine-induced cutaneous responses in healthy adult volunteers

Background: Cetirizine is a highly efficacious and long-acting second-gener ation H-1-receptor antagonist for the treatment of allergic diseases, such as allergic rhinitis and chronic idiopathic urticaria, in adults and childr en. Pharmacologic studies have demonstrated that cetirizine, a racemate mix ture composed of equal amounts of two enantiomers, does not undergo hepatic metabolism to any significant level. The enantiomers are excreted mainly u nchanged, predominantly in the urine and to a lesser extent in the faeces. Methods: The pharmacologic activity and potency of the two enantiomers of c etirizine in the management of allergic skin conditions were investigated b y studying the effect of treatment with 5.0 mg cetirizine; 2.5 mg levocetir izine, the (R)-enantiomer; and 2.5 mg ucb 28557, the (S)-enantiomer, on his tamine-induced wheal and flare response in 18 healthy volunteers. Each trea tment was administered as a single oral dose in randomized, double-blind, a nd crossover manner, and the efficacy of treatment was assessed over a peri od of 32 h, as pel cent inhibition of the histamine-induced wheal and flare areas before treatment. Blood and urine samples were collected in a time-d ependent manner and analyzed for the total amounts of each study drug, to e lucidate their pharmacokinetic profiles. Results: Both cetirizine and levocetirizine caused a marked inhibition of h istamine-induced wheal and flare, whereas ucb 28557 was inactive in this mo del. Inhibition of the wheal response observed for cetirizine and levocetir izine was apparent by 1 h after dosage and lasted for mean durations of 24. 4 and 28.4 h, respectively. In addition, the response for cetirizine and le vocetirizine became maximal by 6 h after treatment, rising to 79.5% and 83. 8%. Similarly, cetirizine and levocetirizine also markedly inhibited the hi stamine-induced flare response. This effect was evident for both drugs by 1 h after dosage and lasted over a mean period of 28.4 and 26.0 h, respectiv ely, for cetirizine and levocetirizine. The inhibitory effect of these comp ounds on histamine-induced flare response was also maximal by approximately 6 h after dosage, peaking at 88.5% and 83.6%, respectively. Statistical ev aluation showed that cetirizine and levocetirizine were equivalent for maxi mum inhibition of histamine-induced wheal and flare. However, levocetirizin e was found to be superior to cetirizine when area under the curve was comp ared. In contrast, ucb 28557 was not found to inhibit histamine-induced whe al and flare responses at any time during the study period. Plasma concentr ations of levocetirizine were found to be approximately double those of ucb 28557 at 4 and 8 h after dosing, and 50 60% of the drugs were excreted unc hanged in urine over a period of 32 h. Conclusions: The finding that, in this model, levocetirizine 2.5 mg has com parable antihistaminic activity to cetirizine 5 mg, whereas its other enant iomer ucb 28557 has no pharmacodynamic effect, suggests that the antihistam inic properties of cetirizine observed in the management of allergic skin c onditions are likely to be attributable to levocetirizine.