Pharmacokinetic-Pharmacodynamic Modelling of the Antihistaminic (H₁) Effect of Bilastine

To model the pharmacokinetic and pharmacodynamic relationship of bilastine, a new histamine H₁ receptor antagonist, from single- and multiple-dose studies in healthy adult subjects.

The pharmacokinetic model was developed from different single-dose and multiple-dose studies. In the single-dose studies, a total of 183 subjects received oral doses of bilastine 2.5, 5, 10, 20, 50, 100, 120, 160, 200 and 220 mg. In the multiple-dose studies, 127 healthy subjects received bilastine 10, 20, 40, 50, 80, 100, 140 or 200 mg/day as multiple doses during a 4-, 7- or 14-day period.

The pharmacokinetic profile of bilastine was investigated using a simultaneous analysis of all concentrationtime data by means of nonlinear mixed-effects modelling population pharmacokinetic software NONMEM® version 6.1.

Plasma concentrations were modelled according to a two-compartment open model with first-order absorption and elimination.

For the pharmacodynamic analysis, the inhibitory effect of bilastine (inhibition of histamine-induced wheal and flare) was assessed on a preselected time schedule, and the predicted typical pharmacokinetic profile (based on the pharmacokinetic model previously developed) was used. An indirect response model was developed to describe the pharmacodynamic relationships between flare or wheal areas and bilastine plasma concentrations.

Finally, once values of the concentration that produced 50% inhibition (IC₅₀) had been estimated for wheal and flare effects, simulations were carried out to predict plasma concentrations for the doses of bilastine 5, 10 and 20 mg at steady state (72–96 hours).

A non-compartmental analysis resulted in linear kinetics of bilastine in the dose range studied. Bilastine was characterized by two-compartmental kinetics with a rapid-absorption phase (first-order absorption rate constant = 1.50 h^-1), plasma peak concentrations were observed at 1 hour following administration and the maximal response was observed at approximately 4 hours or later. Concerning the selected pharmacodynamic model to fit the data (type I indirect response model), this selection is attributable to the presence of inhibitory bilastine plasma concentrations that decrease the input response function, i.e. the production of the skin reaction. This model resulted in the best fit of wheal and flare data. The estimates (with relative standard errors expressed in percentages in parentheses) of the apparent zero-order rate constant for flare or wheal spontaneous appearance (k_in), the first-order rate constant for flare or wheal disappearance (k_out) and bilastine IC₅₀ values were 0.44ng/mL/h (14.60%), 1.09 h^-1 (15.14%) and 5.15 ng/mL (16.16%), respectively, for wheal inhibition, and 11.10 ng/mL/h (8.48%), 1.03 h^-1 (8.35%) and 1.25 ng/mL (14.56%), respectively, for flare inhibition.

The simulation results revealed that bilastine plasma concentrations do not remain over the IC₅₀ value throughout the inter-dose period for doses of 5 and 10 mg. However, with a dose of 20 mg of bilastine administered every 24 hours, plasma concentrations remained over the IC₅₀ value during the considered period for the flare effect, and up to 20 hours for the wheal effect.

Pharmacokinetic and pharmacodynamic relationships of bilastine were reliably described with the use of an indirect response pharmacodynamic model; this led to an accurate prediction of the pharmacodynamic activity of bilastine.