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Application of a dual mechanistic approach to support bilastine dose selection for older adults
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 adult...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452293/ https://www.ncbi.nlm.nih.gov/pubmed/34157202 http://dx.doi.org/10.1002/psp4.12671 |
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author | Kim, Chaejin Lo Re, Valentina Rodriguez, Monica Lukas, John C. Leal, Nerea Campo, Cristina García‐Bea, Aintzane Suarez, Elena Schmidt, Stephan Vozmediano, Valvanera |
author_facet | Kim, Chaejin Lo Re, Valentina Rodriguez, Monica Lukas, John C. Leal, Nerea Campo, Cristina García‐Bea, Aintzane Suarez, Elena Schmidt, Stephan Vozmediano, Valvanera |
author_sort | Kim, Chaejin |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8452293 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-84522932021-09-27 Application of a dual mechanistic approach to support bilastine dose selection for older adults Kim, Chaejin Lo Re, Valentina Rodriguez, Monica Lukas, John C. Leal, Nerea Campo, Cristina García‐Bea, Aintzane Suarez, Elena Schmidt, Stephan Vozmediano, Valvanera CPT Pharmacometrics Syst Pharmacol Research 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. John Wiley and Sons Inc. 2021-08-01 2021-09 /pmc/articles/PMC8452293/ /pubmed/34157202 http://dx.doi.org/10.1002/psp4.12671 Text en © 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Research Kim, Chaejin Lo Re, Valentina Rodriguez, Monica Lukas, John C. Leal, Nerea Campo, Cristina García‐Bea, Aintzane Suarez, Elena Schmidt, Stephan Vozmediano, Valvanera Application of a dual mechanistic approach to support bilastine dose selection for older adults |
title | Application of a dual mechanistic approach to support bilastine dose selection for older adults |
title_full | Application of a dual mechanistic approach to support bilastine dose selection for older adults |
title_fullStr | Application of a dual mechanistic approach to support bilastine dose selection for older adults |
title_full_unstemmed | Application of a dual mechanistic approach to support bilastine dose selection for older adults |
title_short | Application of a dual mechanistic approach to support bilastine dose selection for older adults |
title_sort | application of a dual mechanistic approach to support bilastine dose selection for older adults |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452293/ https://www.ncbi.nlm.nih.gov/pubmed/34157202 http://dx.doi.org/10.1002/psp4.12671 |
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