Abstract

The objective of this study was to evaluate bilastine dosing recommendations in older adults and overcome the limitation of insufficient data from phase I studies in this underrepresented population. This was achieved by integrating bilastine physicochemical, in vitro and in vivo data in young adults and the effect of aging in the pharmacology by means of two alternative approaches: a physiologically-based pharmacokinetic (PBPK) model and a semi-mechanistic population pharmacokinetic (Senescence) model. Intestinal apical efflux and basolateral influx transporters were needed in the PBPK model to capture the observations from young adults after single IV (10mg) and PO (20 mg) doses, supporting the hypothesis of involvement of gut transporters on secretion. The model was then used to extrapolate the PK to elderly subjects considering their specific physiology. Additionally, the Senescence model was develop starting from a published PopPK model, previously applied for pediatrics, and incorporating declining functions on different physiological systems and changes in body composition with aging. Both models were qualified using observed data in a small group of young elderlies (N=16, mean age=68.69 years). The PBPK model was further used to evaluate the dose in older subjects (mean age=80 years) via simulation. The PBPK model supported the hypothesis that basolateral influx and apical efflux transporters are involved in bilastine PK. Both, PBPK and Senescence models indicated that 20 mg QD dose is safe and effective for geriatrics of any age. This approach provides an alternative to generate supplementary data to inform dosing recommendations in underrepresented groups in clinical trials.

By Chaejin Kim, Valentina Lo Re, Monica Rodriguez, John C Lukas, Nerea Leal, Cristina Campo, Aintzane García-Bea, Elena Suarez, Stephan Schmidt,Valvanera Vozmediano