Application of a dual mechanistic approach to support bilastine dose selection for older adults

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 i.v. (10 mg) and p.o. (20 mg) doses, supporting the hypothesis of involvement of gut transporters on secretion. The model was then used to extrapolate the pharmacokinetics (PKs) to elderly subjects considering their specific physiology. Additionally, the Senescence model was develop starting from a published population PK) 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 a 20 mg q.d. dose is safe and effective for geriatrics of any age. This approach provides an alternative to generate supplementary data to inform dosing recommendations in under-represented groups in clinical trials.

FIGURE 1

Overview of the dual physiologically‐based pharmacokinetic model population pharmacokinetic (PBPK‐PopPK) model‐based approach used to evaluate bilastine dosing recommendation in geriatric subjects. GFR, glomerular filtration rate

FIGURE 2

Bilastine PBPK model in young adults. (a) Schematic diagram of proposed intestinal transporters involved in bilastine disposition. (b) Predicted versus observed plasma concentrations after 10 mg single i.v. dose (solid black line: final model; dotted line: model without basolateral influx transporter; grey solid line: model without both basolateral influx and apical efflux transporters; open circles: observations). (c) Predicted versus observed cumulative urine excretion after 10 mg single i.v. dose (solid line: final model; dotted line: model without basolateral influx transporter; grey solid line: model without both basolateral influx and apical efflux transporters; open circle: mean observations. (d) Predicted versus observed plasma concentration after single 20 mg p.o. dose (solid line: final model; dotted line: model without Cs adjustment; open circles‐ observations).

FIGURE 3

Evaluation of the appropriateness of the 20 mg dose in geriatrics with the different models: (a) geriatric PopPK, (b) Senescence, (c) PBPK at mean age of 70 years, and (d) PBPK at mean age of 80 years (dotted line: median PopPK young adults; light grey shaded area: 95% PopPK young adults; solid black lines and dark grey shaded area: median and 95% CI from models (a) Geriatric PopPK, (b) Senescence, and (c, d) PBPK in 70 and 80 year old subjects; light gray lines in (b): individual predictions Senescence model; grey dots: observations). CI, confidence interval; PBPK, physiologically‐based pharmacokinetic; PopPK, population pharmacokinetic