Pharmacokinetic and pharmacodynamic modeling of mizolastine in healthy volunteers with an indirect response model

Objective: The aim of this work was to model the pharmacokinetic and pharma codynamic relationship of mizolastine, a new Hi-receptor antagonist obtaine d from histamine-induced wheal and flare inhibition test. Methods: Fifteen healthy volunteers participated in this double-blind cross over study and randomly received single doses of 5, 10, 15, and 20 mg of mi zolastine and placebo at 1 week intervals. Simultaneous histamine tests and blood samples were performed before and at 9 different times up to 24 hour s after each dosing. Pharmacokinetic and pharmacodynamic modeling were perf ormed subject by subject for the 4 doses altogether by nonlinear regression , first, plasma concentrations were fit according to a two-compartment open model with zero order absorption and first order elimination. Then an indi rect response model with inhibition of the formation rate was developed to describe the pharmacodynamic relationships between flare or wheal raw areas and plasma concentrations with the use of the pharmacokinetic parameters t hat were previously estimated. Results: Mizolastine dose dependently inhibited the histamine-induced wheal and flare formation with a submaximum effect attained after 10 mg. The mea n values of the pharmacodynamic parameters of apparent zero-order rate cons tant for the flare or wheal spontaneous appearance (k(in)), the first-order rate constant for the flare or wheal disappearance, the mizolastine concen tration that produced 50% suppression of the maximum attainable inhibition of k(in), and the maximum attainable inhibition of the effect production we re 14.1 cm(2)/h (coefficient of variation [CV], 32%), 0.68 h(-1) (CV, 24%), 21.1 ng/mL (CV, 77%), and 0.92 (CV, 8%), respectively, for the flare and 1 .9 cm(2)/h (CV, 64%), 0.63 h(-1)(CV, 39%), 43.9 ng/mL (CV, 68%), and 0.87 ( CV, 12%), respectively, for the wheal inhibition. Conclusion: Pharmacokinetic and pharmacodynamic relationships of mizolastin e were reliably described with the use of an indirect pharmacodynamic model ; this led to an accurate prediction of the pharmacodynamic activity of miz olastine.