A pharmacokinetic-pharmacodynamic modelling of the antihistaminic (H1) effects of cetirizine.
OBJECTIVE
The pharmacokinetic-pharmacodynamic modelling developed here characterizes the time course of cetirizine effect on histamine-induced skin reactions (wheal and flare).


METHODS
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.


CONCLUSIONS
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.
Urien
S
S
Laboratoire de Pharmacologie, Faculté de Médecine, Université Paris XII, Créteil, France.
Tillement
J P
JP
Ganem
B
B
Kuch
M D
MD
D000042:Absorption; D000284:Administration, Oral; D001825:Body Fluid Compartments / Q000187:drug effects; D017332:Cetirizine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006632:Histamine / Q000008:administration & dosage; D006634:Histamine H1 Antagonists / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D007279:Injections, Subcutaneous; D008954:Models, Biological; D008956:Models, Chemical; D011237:Predictive Value of Tests; D012882:Skin Tests
D006634:Histamine H1 Antagonists; D006632:Histamine; D017332:Cetirizine