A pharmacokinetic-pharmacodynamic modelling of the antihistaminic (H1) effects of cetirizine.

AIM

The pharmacokinetic-pharmacodynamic modelling developed here characterizes the time course of cetirizine effect on histamine-induced skin reactions (wheal and flare).

METHOD

The model incorporated data from the study of Simons et al. [1993] in which the cetirizine plasma concentrations and the wheal and flare areas were recorded in a group of 6 patients after a 10 mg oral administration.

RESULTS

The peak plasma concentration (>500 ng/ml) was rapidly reached in 1 h and the maximal effects were observed later at approximately 6 h. The cetirizine effect was ascribed to a physiologic indirect response model in which the drug concentration in the central compartment is linked to a response function that describes the inhibition or stimulation of the factors affected, input or output of response control. Cetirizine was characterized by two-compartmental kinetics with a rapid absorption phase (Ka = 1.0-1.4 h(-1)), a rapid distribution phase (alpha = 0.33-0.69 h(-1)) and a slower terminal half-life, 13.2-13.6 h (beta = 0.051-0.052 h(-1)). The total clearance was 1.4-1.5 l/h. Cetirizine effects on flare and wheal were characterized by the inhibition of the input factor (k(in)), the concentrations producing 50% of maximal effect (EC50) were 13 and 40 ng/ml and k(in) were 0.99 and 0.96 h(-1), respectively. These results were then used to simulate repeated daily oral administration of 10 mg cetirizine.

CONCLUSION

At this dosage the histamine-induced flare was at least 80% inhibited at the start of the second administration Thereafter, on successive administrations, the inhibition was even more pronounced and the response control was nearly total.