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 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.

Apixaban and rivaroxaban's physiologically‐based pharmacokinetic model validation in hospitalized patients: A first step for larger use of a priori modeling approach at bed side

“…21 Several studies have highlighted the potential of such an approach in various fields, such as parenteral drug administration 37 or in determining appropriate dosing recommendations in this population. 38,39 Limitations of the present study include the overprediction of PK parameters observed in the VTE population on rivaroxaban 15 mg b.i.d. Indeed, the VTE population in our cohort tends to be younger and has a better renal function, as previously observed in literature.…”

“…The geriatric population is rarely included in the premarketing phases of drug development and PBPK could help to enable individualized dosing regimens and drug therapy guidance in elderly patients 21 . Several studies have highlighted the potential of such an approach in various fields, such as parenteral drug administration 37 or in determining appropriate dosing recommendations in this population 38,39 …”

“… 21 Several studies have highlighted the potential of such an approach in various fields, such as parenteral drug administration 37 or in determining appropriate dosing recommendations in this population. 38 , 39 …”

Key Factors in Effective Patient-Tailored Dosing of Fluoroquinolones in Urological Infections: Interindividual Pharmacokinetic and Pharmacodynamic Variability

“…As an example, alterations in blood flow to main organs and decrease in clearance observed in chronic kidney disease or chronic heart failure can be incorporated in the model to predict changes in the ADME properties of FQs. In addition, mechanistic modeling can be used to explore possible disease effects, test hypotheses, and generate supporting evidences when not enough clinical data are available [107].…”

Predicting transporter mediated drug–drug interactions via static and dynamic physiologically based pharmacokinetic modeling: A comprehensive insight on where we are now and the way forward

“…Recently, many publications related to PBPK modeling where novel transporters are explored came into existence. Kim et al., assuming involvement of novel transporters at the intestinal level, developed the PBPK model for bilastine (Kim et al., 2021). Other transporters, such as (peptide transporter 1) PEPT1 and (plasma membrane monoamine transporter) PMAT, were also being modeled, as they play a vital role for intestinal absorption of drugs such as cefadroxil, lisinopril, and metformin (Tan et al., 2021; Xie et al., 2021; Yang et al., 2021).…”