Model-informed pediatric development applied to bilastine: Analysis of the clinical PK data and confirmation of the dose selected for the target population.

ABSTRACT

Bilastine is a non-sedating second-generation H1 antihistamine approved for treatment of allergic rhinoconjunctivitis (AR) and urticaria (U) in adults at the oral (p.o.) dose of 20 mg once daily (OD). Optimal attributes can be anticipated for its clinical use in pediatrics due to its favorable safety and tolerability and age-independent PD profile. The aim of this work was to characterize bilastine PK in children through population modeling of data from a limited sampling confirmatory clinical trial in children with AR or U. The objective was also to ascertain whether the proposed dose (10 mg/day) in the target pediatric subset aged 2-<12 years matches the systemic exposure seen in adults at the 20 mg/day dose. A popPK model characterizing bilastine PK behavior in children aged from 4 to <12 years treated with 10 mg oral bilastine daily was successfully developed and qualified. No relationship was found between bilastine PK and age or weight; stopping rules pre-stablished to finalize the trial, i.e., model completeness and no dependence of exposure on decreasing age, were thus fulfilled. On a second step, the popPK model in children was linked to the PD model in adults assuming the same PD as described in adults and used to compare the PD outcome between both populations. Finally, an allometric scaling method and a physiological approximation were used to evaluate the suitability of the selected dose in the youngest children, showing that children from 2 years were deemed to belong to the same population as well. The achievement of comparable PK (i.e., within the range) to that observed in adults after the therapeutic dose of 20 mg, together with the achievement of similar PD and additional integrative analysis, served to confirm the validity of the 10 mg daily dose for the target pediatric subset (2 to <12 years).