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 pharmacodynamic relationship of mizolastine, a new H1-receptor antagonist obtained from histamine-induced wheal and flare inhibition test.


METHODS
Fifteen healthy volunteers participated in this double-blind crossover study and randomly received single doses of 5, 10, 15, and 20 mg of mizolastine and placebo at 1 week intervals. Simultaneous histamine tests and blood samples were performed before and at 9 different times up to 24 hours after each dosing. Pharmacokinetic and pharmacodynamic modeling were performed 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 indirect 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 that were previously estimated.


RESULTS
Mizolastine dose dependently inhibited the histamine-induced wheal and flare formation with a submaximum effect attained after 10 mg. The mean values of the pharmacodynamic parameters of apparent zero-order rate constant for the flare or wheal spontaneous appearance (k(in)), the first-order rate constant for the flare or wheal disappearance, the mizolastine concentration that produced 50% suppression of the maximum attainable inhibition of k(in), and the maximum attainable inhibition of the effect production were 14.1 cm2/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 cm2/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.


CONCLUSIONS
Pharmacokinetic and pharmacodynamic relationships of mizolastine were reliably described with the use of an indirect pharmacodynamic model; this led to an accurate prediction of the pharmacodynamic activity of mizolastine.
Deschamps
C
C
Sanofi-Synthelabo, Clinical Metabolism and Pharmacokinetics and Internal Medicine Clinical Development, and INSERM U436, Pitié-Salpétrière Hospital, Paris, France.
Dubruc
C
C
Mentre
F
F
Rosenzweig
P
P
D000284:Administration, Oral; D000328:Adult; D001562:Benzimidazoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001825:Body Fluid Compartments; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006632:Histamine; D006634:Histamine H1 Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008954:Models, Biological; D010919:Placebos; D011237:Predictive Value of Tests; D012882:Skin Tests; D014581:Urticaria / Q000139:chemically induced / Q000517:prevention & control
D001562:Benzimidazoles; D006634:Histamine H1 Antagonists; D010919:Placebos; C076170:mizolastine; D006632:Histamine